Pyrimidinylpiperidinyloxypyridinone analogues as GPR119 modulators

ABSTRACT

Novel compounds of structure Formula I: 
                         
or an enantiomer, a diastereomer, or a pharmaceutically acceptable salt thereof, wherein n 1 , R 1 , R 2 , R 3  and R 4  are defined herein, are provided which are GPR119 G protein-coupled receptor modulators. GPR119 G protein-coupled receptor modulators are useful in treating, preventing, or slowing the progression of diseases requiring GPR119 G protein-coupled receptor modulator therapy. Thus, the disclosure also concerns compositions comprising these novel compounds and methods of treating diseases or conditions related to the activity of the GPR119 G protein-coupled receptor by using any of these novel compounds or a composition comprising any of such novel compounds.

CROSS REFERENCES TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application Ser.No. 61/321,946, filed on Apr. 8, 2010, which is hereby incorporated byreference in its entirety.

FIELD OF THE INVENTION

The present invention provides novel pyridone compounds and analogues,which are modulators of the GPR119 G protein-coupled receptor,compositions containing them, and methods of using them, for example,for the prevention and/or treatment of diseases or disorders associatedwith the activity of the GPR119 G protein-coupled receptor, e.g.,diabetes and obesity.

BACKGROUND OF THE INVENTION

Diabetes mellitus is a serious disease afflicting over 100 millionpeople worldwide. In the United States, there are more than 12 milliondiabetics, with 600,000 new cases diagnosed each year. Diabetes mellitusis a diagnostic term for a group of disorders characterized by abnormalglucose homeostasis resulting in elevated blood sugar. There are manytypes of diabetes, but the two most common are Type 1 (also referred toas insulin-dependent diabetes mellitus or IDDM) and Type 2 (alsoreferred to as non-insulin-dependent diabetes mellitus or NIDDM).

The etiology of the different types of diabetes is not the same;however, everyone with diabetes has two things in common: overproductionof glucose by the liver and little or no ability to move glucose out ofthe blood into the cells where it becomes the body's primary fuel.

People who do not have diabetes rely on insulin, a hormone made in thepancreas, to move glucose from the blood into the cells of the body.However, people who have diabetes either do not produce insulin orcannot efficiently use the insulin they produce; therefore, they cannotmove glucose efficiently into their cells. Glucose accumulates in theblood creating a condition called hyperglycemia, and over time, cancause serious health problems.

Diabetes is a syndrome with interrelated metabolic, vascular, andneuropathic components. The metabolic syndrome, generally characterizedby hyperglycemia, comprises alterations in carbohydrate, fat and proteinmetabolism caused by absent or markedly reduced insulin secretion and/orineffective insulin action. The vascular syndrome consists ofabnormalities in the blood vessels leading to cardiovascular, retinaland renal complications. Abnormalities in the peripheral and autonomicnervous systems are also part of the diabetic syndrome.

Diabetes has also been implicated in the development of kidney disease,eye diseases and nervous-system problems. Kidney disease, also callednephropathy, occurs when the kidney's “filter mechanism” is damaged andprotein leaks into urine in excessive amounts and eventually the kidneyfails. Diabetes is also a leading cause of damage to the retina at theback of the eye and increases risk of cataracts and glaucoma. Finally,diabetes is associated with nerve damage, especially in the legs andfeet, which interferes with the ability to sense pain and contributes toserious infections. Taken together, diabetes complications are one ofthe nation's leading causes of death.

Many people with NIDDM have sedentary lifestyles and are obese; theyweigh approximately 20% more than the recommended weight for theirheight and build. Furthermore, obesity is characterized byhyperinsulinemia and insulin resistance, a feature shared with NIDDM,hypertension and atherosclerosis.

Obesity, which is the result of an imbalance between caloric intake andenergy expenditure, is highly correlated with insulin resistance anddiabetes in experimental animals and human. However, the molecularmechanisms that are involved in obesity-diabetes syndromes are notclear. During early development of obesity, increased insulin secretionbalances insulin resistance and protects patients from hyperglycemia (LeStunff et al., Diabetes, 43:696-702 (1989)). However, over time, β-cellfunction deteriorates and non-insulin-dependent diabetes develops inabout 20% of the obese population (Pederson, P., Diab. Metab. Rev.,5:505-509 (1989)) and (Brancati, F. L. et al., Arch. Intern. Med.,159:957-963 (1999)). Given its high prevalence in modern societies,obesity has thus become the leading risk factor for NIDDM (Hill, J. O.et al., Science, 280:1371-1374 (1998)). However, the factors whichpredispose a fraction of patients to alteration of insulin secretion inresponse to fat accumulation remain unknown. The most common diseaseswith obesity are cardiovascular disease (particularly hypertension),diabetes (obesity aggravates the development of diabetes), gall bladderdisease (particularly cancer) and diseases of reproduction. Research hasshown that even a modest reduction in body weight can correspond to asignificant reduction in the risk of developing coronary heart disease.

Obesity considerably increases the risk of developing cardiovasculardiseases as well. Coronary insufficiency, atheromatous disease, andcardiac insufficiency are at the forefront of the cardiovascularcomplication induced by obesity. It is estimated that if the entirepopulation had an ideal weight, the risk of coronary insufficiency woulddecrease by 25% and the risk of cardiac insufficiency and of cerebralvascular accidents by 35%. The incidence of coronary diseases is doubledin subjects less than 50 years of age who are 30% overweight. Thediabetes patient faces a 30% reduced lifespan. After age 45, people withdiabetes are about three times more likely than people without diabetesto have significant heart disease and up to five times more likely tohave a stroke. These findings emphasize the inter-relations betweenrisks factors for NIDDM, obesity and coronary heart disease as well asthe potential value of an integrated approach involving the treatment ofboth obesity and diabetes (Perry, I. J. et al., BMJ, 310:560-564(1995)).

Type 2 diabetes results from the progressive loss of pancreatic β-cellfunction in the presence of insulin resistance, leading to an overallreduction in insulin output (Prentki, M. et al., “Islet failure in type2 diabetes”, J. Clin. Invest., 116:1802-1812 (2006)). β-cells are thecell type that store and release insulin in response to an elevation inplasma glucose or in response to hormonal signals from the gut followingthe ingestion of food. Evidence suggests that in type 2 diabetics therate of β-cell cell death (apoptosis) exceeds that of new β-celldevelopment, yielding an overall loss in β-cell number (Butler, A. E. etal., “β-cell deficit and increased β-cell apoptosis in humans with type2 diabetes”, Diabetes, 52:102-110 (2003)). β-cell apoptosis may arisefrom persistent elevations in plasma glucose levels (glucotoxicity)and/or plasma lipid levels (lipotoxicity).

G-protein coupled receptors (GPCRs) expressed on β-cells are known tomodulate the release of insulin in response to changes in plasma glucoselevels (Ahren, B, “Autonomic regulation of islet hormonesecretion—Implications for health and disease”, Diabetologia, 43:393-410(2003)). Those GPCRs specifically coupled to the elevation of cAMP viathe G_(s) alpha subunit of G-protein, have been shown to enhanceglucose-stimulated insulin release from β-cells. Cyclic AMP-stimulatingGPCRs on β-cells include the GLP-1, GIP, β2-adrenergic receptors andGPR119. Increasing cAMP concentration in β-cells is known to lead to theactivation of PKA which is thought to prevent the opening of potassiumchannels on the surface of the β-cell. The reduction in K⁺ effluxdepolarizes the β-cell leading to an influx of Ca⁺⁺ which promotes therelease of insulin.

GPR119 (e.g., human GPR119, GENBANK® Accession No AAP72125 and allelesthereof; e.g., mouse GPR119, GENBANK® Accession No. AY288423 and allelesthereof) is a GPCR located at chromosome position Xp26.1 (Fredricksson,R. et al., “Seven evolutionarily conserved human rhodopsin Gprotein-coupled receptors lacking close relatives”, FEBS Lett.,554:381-388 (2003)). The receptor is coupled to Gs, and when stimulated,produces an elevation in cAMP in a variety of cell types includingβ-cell-derived insulinomas (Soga, T. et al., “Lysophosphatidylcholineenhances glucose-dependent insulin secretion via an orphanG-protein-coupled receptor”, Biochem. Biophys. Res. Comm., 326:744-751(2005), PCT Publication Nos. WO 04/065380, WO 04/076413, WO 05/007647,WO 05/007658, WO 05/121121 and WO 06/083491, and EP 1338651). Thereceptor has been shown to be localized to the β-cells of the pancreasin a number of species as well as in specific cell types of thegastrointestinal tract. Activation of GPR119, with agonist ligands suchas lysophosphatidylcholine, produce a glucose dependent increase ininsulin secretion from primary mouse islets and various insulinoma celllines such as NIT-1 and HIT-T15 (Soga, T. et al.,“Lysophosphatidylcholine enhances glucose-dependent insulin secretionvia an orphan G-protein-coupled receptor”, Biochem. Biophys. Res. Comm.,326:744-751 (2005); Chu, Z. L. et al., “A role for β-cell-expressedGPR119 in glycemic control by enhancing glucose-dependent insulinrelease”, Endocrinology, doi:10.1210/en.2006-1608 (2007)).

When activators of GPR119 are administered to either normal mice or micethat are prone to diabetes due to genetic mutation, prior to an oralglucose tolerance test, improvements in glucose tolerance are observed.A short-lived increase in plasma glucagon-like peptide-1 and plasmainsulin levels are also observed in these treated animals (Chu, Z. L. etal., “A role for β-cell-expressed GPR119 in glycemic control byenhancing glucose-dependent insulin release”, Endocrinology,doi:10.1210/en.2006-1608 (2007)). In addition to effects on plasmaglucose levels, GPR119 activators have also been demonstrated to producereductions in acute food intake and to reduce body weight in ratsfollowing chronic administration (Overton, H. A. et al.,“Deorphanization of a G protein-coupled receptor for oleoylethanolamideand its use in the discovery of small-molecule hypophagic agents”, CellMetabolism, 3:167-175 (2006), and PCT Publication Nos. WO 05/007647 andWO 05/007658).

Accordingly, compounds that activate GPR119 could demonstrate a widerange of utilities in treating inflammatory, allergic, autoimmune,metabolic, cancer and/or cardiovascular diseases. PCT Publication Nos.WO 2008/137435 A1, WO 2008/137436 A1, WO 2009/012277 A1, WO 2009/012275A1 (incorporated herein by reference and assigned to present applicant)and WO 2010/009183 A1, disclose compounds that activate GPR119. Thereferences also disclose various processes to prepare these compounds.

It is desirable to find new compounds with improved pharmacologicalcharacteristics compared with known GPR119 activators. For example, itis desirable to find new compounds with improved GPR119 activity andselectivity for GPR119 versus other G protein-coupled receptors (i.e.,5HT2A receptor). It is also desirable to find compounds withadvantageous and improved characteristics in one or more of thefollowing categories:

(a) pharmaceutical properties (i.e., solubility, permeability,amenability to sustained release formulations);

(b) dosage requirements (e.g., lower dosages and/or once-daily dosing);

(c) factors which decrease blood concentration peak-to-troughcharacteristics (i.e., clearance and/or volume of distribution);

(d) factors that increase the concentration of active drug at thereceptor (i.e., protein binding, volume of distribution);

(e) factors that decrease the liability for clinical drug-druginteractions (cytochrome P450 enzyme inhibition or induction, such asCYP 2D6 inhibition, see Dresser, G. K. et al., Clin. Pharmacokinet.,38:41-57 (2000), which is hereby incorporated by reference); and

(f) factors that decrease the potential for adverse side-effects (e.g.,pharmacological selectivity beyond G protein-coupled receptors,potential chemical or metabolic reactivity, limited CNS penetration,ion-channel selectivity). It is especially desirable to find compoundshaving a desirable combination of the aforementioned pharmacologicalcharacteristics.

SUMMARY OF THE INVENTION

In accordance with the present invention, compounds are provided thathave the general structure of Formula I:

or an enantiomer, a diastereomer, or a pharmaceutically acceptable saltthereof, wherein R¹, R², R³ and R⁴ are defined below.

Compounds of the present invention modulate the activity of Gprotein-coupled receptors. Preferably, compounds of the presentinvention modulate the activity of the GPR119 G protein-coupled receptor(“GPR119”). Consequently, the compounds of the present invention may beused in the treatment of multiple diseases or disorders associated withGPR119, such as diabetes and related conditions, microvascularcomplications associated with diabetes, the macrovascular complicationsassociated with diabetes, cardiovascular diseases, Metabolic Syndromeand its component conditions, obesity and other maladies. Examples ofdiseases or disorders associated with the modulation of the GPR119 Gprotein-coupled receptor that can be prevented, modulated, or treatedaccording to the present invention include, but are not limited to,diabetes, hyperglycemia, impaired glucose tolerance, insulin resistance,hyperinsulinemia, retinopathy, neuropathy, nephropathy, delayed woundhealing, atherosclerosis and its sequelae, abnormal heart function,myocardial ischemia, stroke, Metabolic Syndrome, hypertension, obesity,dislipidemia, dyslipidemia, hyperlipidemia, hypertriglyceridemia,hypercholesterolemia, low HDL, high LDL, non-cardiac ischemia, vascularrestenosis, pancreatitis, neurodegenerative disease, lipid disorders,cognitive impairment and dementia, bone disease, HIV protease associatedlipodystrophy and glaucoma.

In addition, the present invention relates to a formulated productwherein the selected formulation is made by using a compound of FormulaI as the only active ingredient or by combining (a) a compound ofFormula I (using any of the compound embodiments listed herein) and (b)an additional active ingredient, for example, dipeptidyl peptidase-IV(DPP4) inhibitor (for example a member selected from saxagliptin,sitagliptin, vildagliptin and alogliptin).

In addition, the present invention relates to a formulated productwherein the selected formulation is made by using a compound of FormulaI as the only active ingredient or by combining (a) a compound ofFormula I (using any of the compound embodiments listed herein) and (b)a dipeptidyl peptidase-IV (DPP4) inhibitor, wherein the DPP4 inhibitoris saxagliptin.

Therefore, in another embodiment, the present invention provides forcompounds of Formula I, pharmaceutical compositions containing suchcompounds, and for methods of using such compounds. In particular, thepresent invention provides a pharmaceutical composition comprising atherapeutically effective amount of a compound of Formula I, alone or incombination with a pharmaceutically acceptable carrier.

Further, in another embodiment, the present invention provides a methodfor preventing, modulating, or treating the progression or onset ofdiseases or disorders associated with the activity of the GPR119 Gprotein-coupled receptor, such as defined above and hereinafter, whereina therapeutically effective amount of a compound of Formula I isadministered to a mammalian, i.e., human, patient in need of treatment.

The compounds of the invention can be used alone, in combination withother compounds of the present invention, or in combination with one ormore other agent(s).

Further, the present invention provides a method for preventing,modulating, or treating the diseases as defined above and hereinafter,wherein a therapeutically effective amount of a combination of acompound of Formula I and another compound of Formula I and/or at leastone other type of therapeutic agent, is administered to a mammalian,i.e., human, patient in need of treatment.

Additionally, the present invention describes compounds that have abeneficial, preferably a two-fold, more preferably, a three-fold,improvement in GPR119 activity/selectivity, in particular, in vivoglucose reduction, in comparison to compounds previously disclosed inthe art, such as those disclosed in PCT Publication No. WO 2009/012275A1.

The present invention also describes compounds that have a beneficialimprovement in metabolic stability, in particular, metabolic stabilityin human liver microsomes, in comparison to compounds previouslydisclosed in the art, such as those disclosed in PCT Publication No. WO2009/012275 A1.

Furthermore, compounds of the present invention show unexpectedadvantages over compounds previously disclosed in the art, such as thosedisclosed in PCT Publication No. WO 2009/012275 A1. The presentcompounds have been shown in an assay(s) to have a desirable combinationof in vivo glucose reduction and metabolic stability in a human livermicrosomal assay. Such compounds should be more useful in the treatment,inhibition or amelioration of one or more diseases or disorders that arediscussed herein.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1. Experimental and simulated powder patterns of5-chloro-4-(1-(5-chloropyrimidin-2-yl)piperidin-4-yloxy)-1-(2-fluoro-4-(methylsulfonyl)phenyl)-pyridin-2(1H)-one,free base, Form A.5-1.

FIG. 2. Experimental and simulated powder patterns of5-chloro-4-(1-(5-chloropyrimidin-2-yl)piperidin-4-yloxy)-1-(2-fluoro-4-(methylsulfonyl)phenyl)-pyridin-2(1H)-one,Form N-2.

FIG. 3. Experimental and simulated powder patterns of5-chloro-4-(1-(5-chloropyrimidin-2-yl)piperidin-4-yloxy)-1-(2-fluoro-4-(methylsulfonyl)phenyl)-pyridin-2(1H)-one,free base, Form AN.5-1.

FIG. 4. Experimental and simulated powder patterns of5-chloro-4-(1-(5-chloropyrimidin-2-yl)piperidin-4-yloxy)-1-(2-fluoro-4-(methylsulfonyl)phenyl)-pyridin-2(1H)-one,free base, Form E.5-1.

FIG. 5. Simulated powder patterns of5-chloro-4-(1-(5-chloropyrimidin-2-yl)piperidin-4-yloxy)-1-(2-fluoro-4-(methylsulfonyl)phenyl)pyridin-2(1H)-one,free base, Form IPA.5-1.

FIG. 6. Experimental powder pattern of5-chloro-4-(1-(5-chloropyrimidin-2-yl)piperidin-4-yloxy)-1-(2-fluoro-4-(methylsulfonyl)phenyl)pyridin-2(1H)-one,material P-6.

FIG. 7. DSC of5-chloro-4-(1-(5-chloropyrimidin-2-yl)piperidin-4-yloxy)-1-(2-fluoro-4-(methylsulfonyl)phenyl)pyridin-2(1H)-one,Form N-2.

FIG. 8. TGA of 5-chloro-4-(1-(5-chloropyrimidin-2-yl)piperidin-4-yloxy)-1-(2-fluoro-4-(methylsulfonyl)phenyl)pyridin-2(1H)-one,Form N-2.

FIG. 9. DSC of5-chloro-4-(1-(5-chloropyrimidin-2-yl)piperidin-4-yloxy)-1-(2-fluoro-4-(methylsulfonyl)phenyl)pyridin-2(1H)-one,material P-6.

FIG. 10. TGA of5-chloro-4-(1-(5-chloropyrimidin-2-yl)piperidin-4-yloxy)-1-(2-fluoro-4-(methylsulfonyl)phenyl)pyridin-2(1H)-one,material P-6.

DETAILED DESCRIPTION

In one embodiment, the present invention provides a compound of FormulaI:

or an enantiomer, diastereomer, tautomer, or salt thereof wherein:

n₁ is 0 or 1;

R₁ is (C₁-C₁₀)alkyl;

R₂ is hydrogen or halo;

R₃ is hydrogen or halo; and

R₄ is halo or halo(C₁-C₃)alkyl.

In one embodiment, the present invention provides a compound or anenantiomer, a diastereomer, or a pharmaceutically acceptable saltthereof, of Formula Ia:

The terms “Formula I”, “Formula Ia” and all embodiments thereof shallinclude enantiomers, diastereomers, solvates and salts thereof(particularly enantiomers, diastereomers and pharmaceutically acceptablesalts thereof).

In another embodiment, the present invention provides a compound ofFormula I or Ia, or an enantiomer, a diastereomer, or a pharmaceuticallyacceptable salt thereof, wherein R₁ is (C₁-C₇)alkyl.

In yet another embodiment, the present invention provides a compound ofFormula I or Ia, or an enantiomer, a diastereomer, or a pharmaceuticallyacceptable salt thereof, wherein R₁ is (C₁-C₆)alkyl.

In still yet another embodiment, the present invention provides acompound of Formula I or Ia, or an enantiomer, a diastereomer, or apharmaceutically acceptable salt thereof, wherein R₁ is (C₁-C₅)alkyl.

In one embodiment, the present invention provides a compound of FormulaI, or an enantiomer, a diastereomer, or a pharmaceutically acceptablesalt thereof, wherein:

n₁ is 1;

R₁ is (C₁-C₅)alkyl;

R₂ is hydrogen or halo;

R₃ is hydrogen or halo; and

R₄ is halo or halo(C₁-C₃)alkyl.

In another embodiment, the present invention provides a compound ofFormula I, or an enantiomer, a diastereomer, or a pharmaceuticallyacceptable salt thereof, wherein:

n₁ is 1;

R₁ is methyl or ethyl;

R₂ is hydrogen or halo;

R₃ is hydrogen or halo; and

R₄ is halo or halo(C₁-C₃)alkyl.

In yet another embodiment, the present invention provides a compound ofFormula I, or an enantiomer, a diastereomer, or a pharmaceuticallyacceptable salt thereof, wherein:

n₁ is 1;

R₁ is methyl or ethyl;

R₂ is hydrogen or halo;

R₃ is hydrogen or F; and

R₄ is halo or halo(C₁-C₃)alkyl.

In still yet another embodiment, the present invention provides acompound of Formula I, or an enantiomer, a diastereomer, or apharmaceutically acceptable salt thereof, wherein:

n₁ is 1;

R₁ is methyl or ethyl;

R₂ is hydrogen or F;

R₃ is hydrogen or F; and

R₄ is halo or halo(C₁-C₃)alkyl.

In one embodiment, the present invention provides a compound of FormulaI, or an enantiomer, a diastereomer, or a pharmaceutically acceptablesalt thereof, wherein:

n₁ is 1;

R₁ is methyl or ethyl;

R₂ is hydrogen or F;

R₃ is hydrogen or F; and

R₄ is Cl or halo(C₁-C₃)alkyl.

In another embodiment, the present invention provides a compound ofFormula I, or an enantiomer, a diastereomer, or a pharmaceuticallyacceptable salt thereof, wherein:

n₁ is 1;

R₁ is methyl or ethyl;

R₂ is hydrogen or F;

R₃ is hydrogen or F; and

R₄ is Cl or —CF₃.

In yet another embodiment, the present invention provides a compound ofFormula I, or an enantiomer, a diastereomer, or a pharmaceuticallyacceptable salt thereof, wherein:

n₁ is 1;

R₁ is methyl or ethyl;

R₂ is hydrogen;

R₃ is hydrogen or F; and

R₄ is Cl or —CF₃.

In still yet another embodiment, the present invention provides acompound of Formula Ia, or an enantiomer, a diastereomer, or apharmaceutically acceptable salt thereof, wherein:

R₁ is (C₁-C₅)alkyl;

R₃ is hydrogen or halo; and

R₄ is halo or halo(C₁-C₃)alkyl.

In one embodiment, the present invention provides a compound of FormulaIa, or an enantiomer, a diastereomer, or a pharmaceutically acceptablesalt thereof, wherein:

R₁ is methyl or ethyl;

R₃ is hydrogen or halo; and

R₄ is halo or halo(C₁-C₃)alkyl.

In another embodiment, the present invention provides a compound ofFormula Ia, or an enantiomer, a diastereomer, or a pharmaceuticallyacceptable salt thereof, wherein:

R₁ is methyl or ethyl;

R₃ is hydrogen or F; and

R₄ is halo or halo(C₁-C₃)alkyl.

In another embodiment, the present invention provides a compound ofFormula Ia, or an enantiomer, a diastereomer, or a pharmaceuticallyacceptable salt thereof, wherein:

R₁ is methyl or ethyl;

R₃ is hydrogen or F; and

R₄ is Cl or halo(C₁-C₃)alkyl.

In another embodiment, the present invention provides a compound ofFormula Ia, or an enantiomer, a diastereomer, or a pharmaceuticallyacceptable salt thereof, wherein:

R₁ is methyl or ethyl;

R₃ is hydrogen or F; and

R₄ is Cl or —CF₃.

In one embodiment, the present invention provides a compound of FormulaIa, or an enantiomer, a diastereomer, or a pharmaceutically acceptablesalt thereof, wherein:

R₁ is methyl;

R₃ is hydrogen or F; and

R₄ is Cl or —CF₃.

In another embodiment, the present invention provides a compound ofFormula I, or an enantiomer, a diastereomer, or a pharmaceuticallyacceptable salt thereof, wherein the compound is selected from one ofthe examples, preferably Examples 1-6 and 8, more preferably, Examples4, 5 and 8.

For each of the embodiments described in this application, further andmore particular values of the terms used in each of the embodiments maybe selected. These values may be used individually in any of theembodiments or in any combination. It is noted that for any occurrencesof “═O”, these may be used with suitable accommodation in the bondstructure at that site as will be appreciated by those skilled in theart.

In one embodiment, the present invention relates to methods ofmodulating the activity of the GPR119 G protein-coupled receptorcomprising administering to a mammalian patient, for example, a humanpatient, in need thereof a therapeutically effective amount of acompound of Formula I or Ia, preferably, a compound selected from one ofthe examples, more preferably Examples 1-6 and 8, even more preferably,Examples 4, 5 and 8, alone, or optionally, in combination with anothercompound of the present invention and/or at least one other type oftherapeutic agent.

In one embodiment, the present invention relates to a method forpreventing, modulating, or treating the progression or onset of diseasesor disorders associated with the activity of the GPR119 Gprotein-coupled receptor comprising administering to a mammalianpatient, for example, a human patient, in need of prevention,modulation, or treatment a therapeutically effective amount of acompound of Formula I or Ia, preferably, a compound selected from one ofthe examples, more preferably Examples 1-6 and 8, even more preferably,Examples 4, 5 and 8, alone, or, optionally, in combination with anothercompound of the present invention and/or at least one other type oftherapeutic agent.

Examples of diseases or disorders associated with the activity of theGPR119 G protein-coupled receptor that can be prevented, modulated, ortreated according to the present invention include, but are not limitedto, diabetes, hyperglycemia, impaired glucose tolerance, insulinresistance, hyperinsulinemia, retinopathy, neuropathy, nephropathy,delayed wound healing, atherosclerosis and its sequelae, abnormal heartfunction, myocardial ischemia, stroke, Metabolic Syndrome, hypertension,obesity, dislipidemia, dyslipidemia, hyperlipidemia,hypertriglyceridemia, hypercholesterolemia, low HDL, high LDL,non-cardiac ischemia, infection, cancer, vascular restenosis,pancreatitis, neurodegenerative disease, lipid disorders, cognitiveimpairment and dementia, bone disease, HIV protease associatedlipodystrophy and glaucoma.

In another embodiment, the present invention relates to a method forpreventing, modulating, or treating the progression or onset ofdiabetes, hyperglycemia, obesity, dyslipidemia, hypertension andcognitive impairment comprising administering to a mammalian patient,for example, a human patient, in need of prevention, modulation, ortreatment a therapeutically effective amount of a compound of Formula Ior Ia, preferably, a compound selected from one of the examples, morepreferably Examples 1-6 and 8, even more preferably, Examples 4, 5 and8, alone, or, optionally, in combination with another compound of thepresent invention and/or at least one other type of therapeutic agent.

In another embodiment, the present invention relates to a method forpreventing, modulating, or treating the progression or onset ofdiabetes, comprising administering to a mammalian patient, for example,a human patient, in need of prevention, modulation, or treatment atherapeutically effective amount of a compound of Formula I or Ia,preferably, a compound selected from one of the examples, morepreferably Examples 1-6 and 8, even more preferably, Examples 4, 5 and8, alone, or, optionally, in combination with another compound of thepresent invention and/or at least one other type of therapeutic agent.

In yet another embodiment, the present invention relates to a method forpreventing, modulating, or treating the progression or onset ofhyperglycemia comprising administering to a mammalian patient, forexample, a human patient, in need of prevention, modulation, ortreatment a therapeutically effective amount of a compound of Formula Ior Ia, preferably, a compound selected from one of the examples, morepreferably Examples 1-6 and 8, even more preferably, Examples 4, 5 and8, alone, or, optionally, in combination with another compound of thepresent invention and/or at least one other type of therapeutic agent.

In still yet another embodiment, the present invention relates to amethod for preventing, modulating, or treating the progression or onsetof obesity comprising administering to a mammalian patient, for example,a human patient, in need of prevention, modulation, or treatment atherapeutically effective amount of a compound of Formula I or Ia,preferably, a compound selected from one of the examples, morepreferably Examples 1-6 and 8, even more preferably, Examples 4, 5 and8, alone, or, optionally, in combination with another compound of thepresent invention and/or at least one other type of therapeutic agent.

In one embodiment, the present invention relates to a method forpreventing, modulating, or treating the progression or onset ofdyslipidemia comprising administering to a mammalian patient, forexample, a human patient, in need of prevention, modulation, ortreatment a therapeutically effective amount of a compound of Formula Ior Ia, preferably, a compound selected from one of the examples, morepreferably Examples 1-6 and 8, even more preferably, Examples 4, 5 and8, alone, or, optionally, in combination with another compound of thepresent invention and/or at least one other type of therapeutic agent.

In another embodiment, the present invention relates to a method forpreventing, modulating, or treating the progression or onset ofhypertension comprising administering to a mammalian patient, forexample, a human patient, in need of prevention, modulation, ortreatment a therapeutically effective amount of a compound of Formula Ior Ia, preferably, a compound selected from one of the examples, morepreferably Examples 1-6 and 8, even more preferably, Examples 4, 5 and8, alone, or, optionally, in combination with another compound of thepresent invention and/or at least one other type of therapeutic agent.

In another embodiment, the present invention relates to a formulatedproduct, for example a spray dried dispersion, wherein the selectedformulation is made by combining (a) a compound of Formula I or Ia,preferably, a compound selected from one of the examples, morepreferably Examples 1-6 and 8, even more preferably, Examples 4, 5 and 8(using any of the compound embodiments listed above), and (b) adipeptidyl peptidase-IV (DPP4) inhibitor (for example, a member selectedfrom saxagliptin, sitagliptin, vildagliptin and alogliptin).

In another embodiment, the present invention relates to a formulatedproduct, for example a spray dried dispersion, wherein the selectedformulation is made by combining (a) a compound of Formula I or Ia,preferably, a compound selected from one of the examples, morepreferably Examples 1-6 and 8, even more preferably, Examples 4, 5 and 8(using any of the compound embodiments listed above), and (b) adipeptidyl peptidase-IV (DPP4) inhibitor, wherein the DPP4 inhibitor issaxagliptin.

The invention may be embodied in other specific forms without departingfrom the spirit or essential attributes thereof. This invention alsoencompasses all combinations of alternative aspects of the inventionnoted herein. It is understood that any and all embodiments of thepresent invention may be taken in conjunction with any other embodimentto describe additional embodiments of the present invention.Furthermore, any elements of an embodiment may be combined with any andall other elements from any of the embodiments to describe additionalembodiments.

DEFINITIONS

The compounds herein described may have asymmetric centers. Compounds ofthe present invention containing an asymmetrically substituted atom maybe isolated in optically active or racemic forms. It is well known inthe art how to prepare optically active forms, such as by resolution ofracemic forms or by synthesis from optically active starting materials.Many geometric isomers of olefins, C═N double bonds, and the like canalso be present in the compounds described herein, and all such stableisomers are contemplated in the present invention. Cis and transgeometric isomers of the compounds of the present invention aredescribed and may be isolated as a mixture of isomers or as separatedisomeric forms. All chiral, diastereomeric, racemic forms and allgeometric isomeric forms of a structure are intended, unless thespecific stereochemistry or isomeric form is specifically indicated.

One enantiomer of a compound of Formula I may display superior activitycompared with the other. Thus, all of the stereochemistries areconsidered to be a part of the present invention. When required,separation of the racemic material can be achieved by high performanceliquid chromatography (HPLC) using a chiral column or by a resolutionusing a resolving agent such as camphonic chloride as in Young, S. D. etal., Antimicrobial Agents and Chemotherapy, 2602-2605 (1995).

To the extent that compounds of Formula I, and salts thereof, may existin their tautomeric form, all such tautomeric forms are contemplatedherein as part of the present invention.

When any variable (e.g., ═O) occurs more than one time in anyconstituent or formula for a compound, its definition at each occurrenceis independent of its definition at every other occurrence. Thus, forexample, if a group is shown to be substituted with (═O)_(n1) and n1 is0 or 1, then said group may optionally be substituted with up to one ═Ogroup. Also, combinations of substituents and/or variables arepermissible only if such combinations result in stable compounds.

Combinations of substituents and/or variables are permissible only ifsuch combinations result in stable compounds.

As used herein, “alkyl” is intended to include both branched andstraight-chain saturated aliphatic hydrocarbon groups in the normalchain, such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl,isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl,2,2,4-trimethyl-pentyl, nonyl, decyl, the various branched chain isomersthereof.

“Halo” or “halogen” as used herein refers to fluoro, chloro, bromo, andiodo; and “haloalkyl” is intended to include both branched andstraight-chain saturated aliphatic hydrocarbon groups, for example CF₃,having the specified number of carbon atoms, substituted with 1 or morehalogen (for example —C_(v)F_(w), where v=1 to 3 and w=1 to (2v+1)).

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio.

As used herein, “pharmaceutically acceptable salts” refer to derivativesof the disclosed compounds wherein the parent compound is modified bymaking acid or base salts thereof. Examples of pharmaceuticallyacceptable salts include, but are not limited to, mineral or organicacid salts of basic residues such as amines; alkali or organic salts ofacidic residues such as carboxylic acids; and the like. Thepharmaceutically acceptable salts include the conventional non-toxicsalts or the quaternary ammonium salts of the parent compound formed,for example, from non-toxic inorganic or organic acids. For example,such conventional non-toxic salts include those derived from inorganicacids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric,nitric and the like; and the salts prepared from organic acids such asacetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric,citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic,benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric,toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic,and the like.

The pharmaceutically acceptable salts of the present invention can besynthesized from the parent compound by conventional chemical methods.Generally, such salts can be prepared by reacting the free acid or baseforms of these compounds with a stoichiometric amount of the appropriatebase or acid in water or in an organic solvent, or in a mixture of thetwo; generally, nonaqueous media like ether, ethyl acetate, ethanol,isopropanol, or acetonitrile are preferred. Lists of suitable salts arefound in Remington's Pharmaceutical Sciences, 17th Edition, MackPublishing Company, Easton, Pa., p. 1418 (1985), the disclosure of whichis hereby incorporated by reference.

Any compound that can be converted in vivo to provide the bioactiveagent (i.e., a compound of Formula I) is a prodrug within the scope andspirit of the invention.

In addition, compounds of Formula I or Ia, preferably, a compoundselected from one of the examples, more preferably Examples 1-6 and 8,even more preferably, Examples 4, 5 and 8, are, subsequent to theirpreparation, preferably isolated and purified to obtain a compositioncontaining an amount by weight equal to or greater than 99% of saidcompound (“substantially pure” compound), which is then used orformulated as described herein. Such “substantially pure” compounds ofFormula I or Ia, preferably, a compound selected from one of theexamples, more preferably Examples 1-6 and 8, even more preferably,Examples 4, 5 and 8, are also contemplated herein as part of the presentinvention.

All stereoisomers of the compounds of the instant invention arecontemplated, either in admixture or in pure or substantially pure form.The compounds of the present invention can have asymmetric centers atany of the sulfur or carbon atoms including any one of the Rsubstituents and/or exhibit polymorphism. Consequently, compounds of thepresent invention can exist in enantiomeric, or diastereomeric forms, orin mixtures thereof. The processes for preparation can utilizeracemates, enantiomers, or diastereomers as starting materials. Whendiastereomeric or enantiomeric products are prepared, they can beseparated by conventional methods for example, chromatographic orfractional crystallization.

The invention also includes isotopically-labeled compounds of theinvention, wherein one or more atoms is replaced by an atom having thesame atomic number, but an atomic mass or mass number different from theatomic mass or mass number usually found in nature. Examples of isotopessuitable for inclusion in the compounds of the invention includeisotopes of hydrogen, such as ²H and ³H, carbon such as ¹¹C, ¹³C, and¹⁴C, chlorine, such as ³⁶Cl, fluorine such as ¹⁸F, iodine, such as ¹²³Iand ¹²⁵I, nitrogen, such as ¹³N and ¹⁵N, oxygen, such as ¹⁵O, ¹⁷O, and¹⁸O, phosphorus, such as ³²P, and sulfur, such as ³⁵S. Certainisotopically-labeled compounds of the invention, for example, thoseincorporating a radioactive isotope, are useful in drug and/or substratetissue distribution studies. The radioactive isotopes tritium, ³H, andcarbon-14, ¹⁴C, are particularly useful for this purpose in view oftheir ease of incorporation and ready means of detection. Substitutionwith heavier isotopes such as deuterium, ²H, may afford certaintherapeutic advantages resulting from greater metabolic stability, forexample, increase in vivo half-life or reduced dosage requirements, andhence may be preferred in some circumstances. Substitution with positronemitting isotopes, such as ¹¹C, ¹⁸F, ¹⁵O, and ¹³N, can be useful inPositron Emission Topography (PET) studies for examining substratereceptor occupancy.

Isotopically-labeled compounds of the invention can generally beprepared by conventional techniques known to those skilled in the art orby processes analogous to those described herein, using an appropriateisotopically-labeled reagent in place of the non-labeled reagentotherwise employed.

“Stable compound” and “stable structure” are meant to indicate acompound that is sufficiently robust to survive isolation to a usefuldegree of purity from a reaction mixture, and formulation into anefficacious therapeutic agent. The present invention is intended toembody stable compounds.

“Therapeutically effective amount” is intended to include an amount of acompound of the present invention alone or an amount of the combinationof compounds claimed or an amount of a compound of the present inventionin combination with other active ingredients effective to modulateGPR119 or effective to treat or prevent various disorders.

As used herein, “treating” or “treatment” cover the treatment of adisease-state in a mammal, particularly in a human, and include: (a)preventing the disease-state from occurring in a mammal, in particular,when such mammal is predisposed to the disease-state but has not yetbeen diagnosed as having it; (b) modulating the disease-state, i.e.,arresting it development; and/or (c) relieving the disease-state, i.e.,causing regression of the disease state.

As used herein “solvate” refers to a crystalline form of a molecule,atom, and/or ions that further contains molecules of a solvent orsolvents incorporated into the crystalline structure. The solventmolecules in the solvate may be present in a regular arrangement and/ora non-ordered arrangement. The solvate may comprise either astoichiometric or nonstoichiometric amount of the solvent molecules. Forexample, a solvate with a nonstoichiometric amount of solvent moleculesmay result from partial loss of solvent from the solvate.

The names used herein to characterize a specific form, e.g., “N-2”,should not be considered limiting with respect to any other substancepossessing similar or identical physical and chemical characteristics,but rather it should be understood that these designations are mereidentifiers that should be interpreted according to the characterizationinformation also presented herein.

The present invention provides, at least in part, crystalline forms ofthe free base of5-chloro-4-(1-(5-chloropyrimidin-2-yl)piperidin-4-yloxy)-1-(2-fluoro-4-(methylsulfonyl)phenyl)pyridin-2(1H)-one,as a novel material, in particular in a pharmaceutically acceptableform. In certain preferred embodiments, crystalline forms of the freebase are in substantially pure form. Preferred embodiments ofcrystalline forms of the free base are disclosed in Example 13 as theA.5-1, N-2, AN.5-1, E.5-1, IPA-1, P-6, SC-3 and BZ-3 Forms.

As used herein “polymorph” refers to crystalline forms having the samechemical composition but different spatial arrangements of themolecules, atoms, and/or ions forming the crystal.

As used herein “amorphous” refers to a solid form of a molecule, atom,and/or ions that is not crystalline.

Samples of the crystalline forms may be provided with substantially purephase homogeneity, indicating the presence of a dominant amount of asingle crystalline form and optionally minor amounts of one or moreother crystalline forms. The presence of more than one crystalline formin a sample may be determined by techniques such as powder X-raydiffraction (PXRD) or solid state nuclear magnetic resonancespectroscopy (SSNMR). For example, the presence of extra peaks in thecomparison of an experimentally measured PXRD pattern with a simulatedPXRD pattern may indicate more than one crystalline form in the sample.The simulated PXRD may be calculated from single crystal X-ray data. SeeSmith, D. K., “A FORTRAN Program for Calculating X-Ray PowderDiffraction Patterns”, Lawrence Radiation Laboratory, Livermore, Calif.,UCRL-7196 (April 1963).

Preferably, the crystalline form has substantially pure phasehomogeneity as indicated by less than 10%, preferably less than 5%, andmore preferably less than 2% of the total peak area in theexperimentally measured PXRD pattern arising from the extra peaks thatare absent from the simulated PXRD pattern. Most preferred is acrystalline form having substantially pure phase homogeneity with lessthan 1% of the total peak area in the experimentally measured PXRDpattern arising from the extra peaks that are absent from the simulatedPXRD pattern.

Procedures for the preparation of crystalline forms are known in theart. The crystalline forms may be prepared by a variety of methods,including for example, crystallization or recrystallization from asuitable solvent, sublimation, growth from a melt, solid statetransformation from another phase, crystallization from a supercriticalfluid, and jet spraying. Techniques for crystallization orrecrystallization of crystalline forms from a solvent mixture include,for example, evaporation of the solvent, decreasing the temperature ofthe solvent mixture, crystal seeding a supersaturated solvent mixture ofthe molecule and/or salt, freeze drying the solvent mixture, andaddition of antisolvents (countersolvents) to the solvent mixture.

The forms may be characterized and distinguished using single crystalX-ray diffraction, which is based on unit cell and intensitymeasurements of a single crystal of a form at a fixed analyticaltemperature. A detailed description of unit cell and intensity analysisis provided in Stout et al., Chapter 3, X-Ray Structure Determination: APractical Guide, MacMillan Co., New York (1968), which is hereinincorporated by reference. Alternatively, the unique arrangement ofatoms in spatial relation within the crystalline lattice may becharacterized according to the observed fractional atomic coordinates.See Stout et al. reference for experimental determination of fractionalcoordinates for structural analysis. Another means of characterizing thecrystalline structure is by powder X-ray diffraction analysis in whichthe experimental or observed diffraction profile is compared to asimulated profile representing pure powder material, both at the sameanalytical temperature, and measurements for the subject formcharacterized as a series of 2θ values and intensities.

The term “negligible weight loss”, as employed herein, as characterizedby TGA indicates the presence of a neat (non-solvated) crystal form.

In one embodiment of the invention, a crystalline form of5-chloro-4-(1-(5-chloropyrimidin-2-yl)piperidin-4-yloxy)-1-(2-fluoro-4-(methylsulfonyl)phenyl)-pyridin-2(1H)-one is provided in substantially pureform. This crystalline form may be employed in pharmaceuticalcompositions which may optionally include one or more other componentsselected, for example, from the group consisting of excipients,carriers, and one of other active pharmaceutical ingredients or activechemical entities of different molecular structures.

Preferably, the crystalline form has substantially pure phasehomogeneity as indicated by less than 10%, preferably less than 5%, andmore preferably less than 2% of the total peak area in theexperimentally measured PXRD pattern arising from the extra peaks thatare absent from the simulated PXRD pattern. Most preferred is acrystalline form having substantially pure phase homogeneity with lessthan 1% of the total peak area in the experimentally measured PXRDpattern arising from the extra peaks that are absent from the simulatedPXRD pattern.

In another embodiment, a composition is provided consisting essentiallyof the crystalline forms of5-chloro-4-(1-(5-chloropyrimidin-2-yl)piperidin-4-yloxy)-1-(2-fluoro-4-(methylsulfonyl)phenyl)pyridin-2(1H)-one.The composition of this embodiment may comprise at least 90 weight % ofthe form, based on its weight in the composition.

The presence of reaction impurities and/or processing impurities may bedetermined by analytical techniques known in the art, such as, forexample, chromatography, nuclear magnetic resonance spectroscopy, massspectrometry or infrared spectroscopy.

Crystalline forms may be prepared by a variety of methods, including forexample, crystallization or recrystallization from a suitable solvent,sublimation, growth from a melt, solid state transformation from anotherphase, crystallization from a supercritical fluid, and jet spraying.Techniques for crystallization or recrystallization of crystalline formsfrom a solvent mixture include, for example, evaporation of the solvent,decreasing the temperature of the solvent mixture, crystal seeding asupersaturated solvent mixture of the molecule and/or salt, freezedrying the solvent mixture, and addition of antisolvents(countersolvents) to the solvent mixture. High throughputcrystallization techniques may be employed to prepare crystalline formsincluding polymorphs.

Crystals of drugs, including polymorphs, methods of preparation, andcharacterization of drug crystals are discussed in Byrn, S. R. et al.,Solid-State Chemistry of Drugs, 2nd Edition, SSCI, West Lafayette, Ind.(1999).

For crystallization techniques that employ solvent, the choice ofsolvent or solvents is typically dependent upon one or more factors,such as solubility of the compound, crystallization technique, and vaporpressure of the solvent. Combinations of solvents may be employed; forexample, the compound may be solubilized into a first solvent to afforda solution, followed by the addition of an antisolvent to decrease thesolubility of the compound in the solution and to afford the formationof crystals. An “antisolvent” is a solvent in which the compound has lowsolubility. Suitable solvents for preparing crystals include polar andnonpolar solvents.

In one method to prepare crystals,5-chloro-4-(1-(5-chloropyrimidin-2-yl)piperidin-4-yloxy)-1-(2-fluoro-4-(methylsulfonyl)phenyl)pyridin-2(1H)-oneis suspended and/or stirred in a suitable solvent to afford a slurry,which may be heated to promote dissolution. The term “slurry”, as usedherein, means a saturated solution of the free base, which may alsocontain an additional amount of the compound to afford a heterogeneousmixture of the compound and a solvent at a given temperature. Suitablesolvents in this regard include, for example, polar aprotic solvents andpolar protic solvents, and mixtures of two or more of these, asdisclosed herein.

Seed crystals may be added to any crystallization mixture to promotecrystallization. As will be clear to the skilled artisan, seeding isused as a means of controlling growth of a particular crystalline formor as a means of controlling the particle size distribution of thecrystalline product. Accordingly, calculation of the amount of seedsneeded depends on the size of the seed available and the desired size ofan average product particle as described, for example, in Mullin, J. W.et al., “Programmed cooling of batch crystallizers”, ChemicalEngineering Science, 26:369-377 (1971). In general, seeds of small sizeare needed to effectively control the growth of crystals in the batch.Seeds of small size may be generated by sieving, milling, or micronizingof larger crystals, or by micro-crystallization of solutions. Careshould be taken that milling or micronizing of crystals does not resultin any change in crystallinity from the desired crystal form (i.e.,change to amorphous or to another polymorph).

A cooled mixture may be filtered under vacuum, and the isolated solidsmay be washed with a suitable solvent, such as cold recrystallizationsolvent, and dried under a nitrogen purge to afford the desiredcrystalline form. The isolated solids may be analyzed by a suitablespectroscopic or analytical technique, such as SSNMR, DSC, PXRD, or thelike, to assure formation of the preferred crystalline form of theproduct. The resulting crystalline form is typically produced in anamount of greater than about 70 weight % isolated yield, but preferablygreater than 90 weight % based on the weight of5-chloro-4-(1-(5-chloropyrimidin-2-yl)piperidin-4-yloxy)-1-(2-fluoro-4-(methylsulfonyl)phenyl)pyridin-2(1H)-oneoriginally employed in the crystallization procedure. The product may beco-milled or passed through a mesh screen to de-lump the product, ifnecessary.

Crystalline forms may be prepared directly from the reaction medium ofthe final process step for preparing5-chloro-4-(1-(5-chloropyrimidin-2-yl)piperidin-4-yloxy)-1-(2-fluoro-4-(methylsulfonyl)phenyl)pyridin-2(1H)-one.This may be achieved, for example, by employing in the final processstep a solvent or mixture of solvents from which the free base may becrystallized. Alternatively, crystalline forms may be obtained bydistillation or solvent addition techniques. Suitable solvents for thispurpose include any of those solvents described herein, including proticpolar solvents, such as alcohols, and aprotic polar solvents, such asketones.

By way of general guidance, the reaction mixture may be filtered toremove any undesired impurities, inorganic salts, and the like, followedby washing with reaction or crystallization solvent. The resultingsolution may be concentrated to remove excess solvent or gaseousconstituents. If distillation is employed, the ultimate amount ofdistillate collected may vary, depending on process factors including,for example, vessel size, stirring capability, and the like. By way ofgeneral guidance, the reaction solution may be distilled to about 1/10the original volume before solvent replacement is carried out. Thereaction may be sampled and assayed to determine the extent of thereaction and the wt % product in accordance with standard processtechniques. If desired, additional reaction solvent may be added orremoved to optimize reaction concentration. Preferably, the finalconcentration is adjusted to about 50 wt % at which point a slurrytypically results.

It may be preferable to add solvents directly to the reaction vesselwithout distilling the reaction mixture. Although the finalconcentration may vary depending on desired purity, recovery and thelike, the final concentration of the free base in solution is preferablyabout 4% to about 7%. The reaction mixture may be stirred followingsolvent addition and simultaneously warmed. By way of illustration, thereaction mixture may be stirred for about 1 hour while warming to about70° C. The reaction is preferably filtered hot and washed with eitherthe reaction solvent, the solvent added or a combination thereof. Seedcrystals may be added to any crystallization solution to initiatecrystallization.

The various forms described herein may be distinguishable from oneanother through the use of various analytical techniques known to one ofordinary skill in the art. Such techniques include, but are not limitedto, X-ray powder diffraction (PXRD). Specifically, the forms may becharacterized and distinguished using single crystal X-ray diffraction,which is based on unit cell measurements of a single crystal of a givenform at a fixed analytical temperature. A detailed description of unitcells is provided in Stout et al. Chapter 3, X-Ray StructureDetermination: A Practical Guide, MacMillan Co., New York (1968), whichis herein incorporated by reference. Alternatively, the uniquearrangement of atoms in spatial relation within the crystalline latticemay be characterized according to the observed fractional atomiccoordinates. Another means of characterizing the crystalline structureis by powder X-ray diffraction analysis in which the diffraction profileis compared to a simulated profile representing pure powder material,both run at the same analytical temperature, and measurements for thesubject form characterized as a series of 2θ values (usually four ormore).

Other means of characterizing the form may be used, such as solid statenuclear magnetic resonance (SSNMR) spectroscopy, differential scanningcalorimetry (DSC), thermography and gross examination of the crystallineor amorphous morphology. These parameters may also be used incombination to characterize the subject form.

One of ordinary skill in the art will appreciate that an X-raydiffraction pattern may be obtained with a measurement error that isdependent upon the measurement conditions employed. In particular, it isgenerally known that intensities in an X-ray diffraction pattern mayfluctuate depending upon measurement conditions employed and the shapeor morphology of the crystal. It should be further understood thatrelative intensities may also vary depending upon experimentalconditions and, accordingly, the exact order of intensity should not betaken into account. Additionally, a measurement error of diffractionangle for a conventional X-ray diffraction pattern is typically about0.2° or less, preferably about 0.1° (as discussed hereinafter), and suchdegree of measurement error should be taken into account as pertainingto the aforementioned diffraction angles. Consequently, it is to beunderstood that the crystal forms of the instant invention are notlimited to the crystal forms that provide X-ray diffraction patternscompletely identical to the X-ray diffraction patterns depicted in theaccompanying Figures disclosed herein. Any crystal forms that provideX-ray diffraction patterns substantially identical to those disclosed inthe accompanying Figures fall within the scope of the present invention.The ability to ascertain substantial identities of X-ray diffractionpatterns is within the purview of one of ordinary skill in the art.

Synthesis

The compounds of the present invention can be prepared in a number ofways well known to one skilled in the art of organic synthesis. Thecompounds of the present invention can be synthesized using the methodsdescribed below, together with synthetic methods known in the art ofsynthetic organic chemistry, or variations thereof as appreciated bythose skilled in the art. Preferred methods include, but are not limitedto, those described below. All references cited herein are herebyincorporated in their entirety by reference.

The novel compounds of Formula I may be prepared using the reactions andtechniques described in this section. The reactions are performed insolvents appropriate to the reagents and materials employed and aresuitable for the transformations being effected. Also, in thedescription of the synthetic methods described below, it is to beunderstood that all proposed reaction conditions, including solvent,reaction atmosphere, reaction temperature, duration of the experimentand workup procedures, are chosen to be the conditions standard for thatreaction, which should be readily recognized by one skilled in the art.One skilled in the art of organic synthesis understands that thefunctionality present on various portions of the molecule must becompatible with the reagents and reactions proposed. Not all compoundsof Formula I falling into a given class may be compatible with some ofthe reaction conditions required in some of the methods described. Suchrestrictions to the substituents, which are compatible with the reactionconditions, will be readily apparent to one skilled in the art andalternate methods must be used.

Compounds of Formula I may be prepared by procedures depicted inScheme 1. Gimeracil, obtained from commercial sources, can be reactedwith intermediate A, obtained from commercial sources, in the presenceof a base such as K₂CO₃ or sodium hydride in a suitable solvent such asDMF, THF etc. or intermediate B, obtained from commercial sources, usingMitsunobu reaction conditions well known to one skilled in the art oforganic synthesis to yield intermediate C. Coupling of intermediate Cand intermediate D, obtained from commercial sources or synthesized by astraight forward alkylation of the appropriately substituted commercialthiophenol with R₁Br and then oxidation to the sulfone or sulfoxide withmCPBA, can be accomplished in the presence of a ligand such as but notlimited to 8-hydroxyquinoline, CuI (I), and a base such as K₂CO₃ in asuitable solvent such as DMF, DMSO, etc., at an elevated temperature toyield intermediate E. Alternatively, the coupling of intermediate C andintermediate D, when X is F, can be accomplished in the presence of abase such as but not limited to sodium hydride in a suitable solventsuch as DMF. Removal of the protecting group from intermediate E can becarried out with appropriate reagents well known to those skilled in theart (for specific details see Greene et al., Protecting Groups inOrganic Synthesis, John Wiley & Sons Inc. (1991)). The deprotectedproduct, intermediate F, can then be treated with intermediate G, whichare commercially available or can be prepared by many methods known inthe art, in the presence of a base, such as triethylamine or K₂CO₃,which are routine for those skilled in the art of organic synthesis toafford compounds of Formula I.

Alternatively, compounds of Formula I may be prepared by proceduresdepicted in Scheme 2. Gimeracil can be reacted with intermediate D inthe presence of a ligand such as but not limited to 1,10-phenanthroline,CuI (I), and a base such as K₂CO₃, in a suitable solvent such as DMF,DMSO, etc., at an elevated temperature to yield intermediate H. Couplingof the intermediate H and intermediates A or B can be accomplished usingconditions described above for step 1 of Scheme 1 to yield intermediateE. Intermediate E can then be carried forward according to Scheme 1 toprovide the final products of Formula I. Alternatively, compounds ofFormula 1 may be obtained by coupling intermediate K with intermediate Husing Mitsunobu reaction conditions well known to one skilled in the artof organic synthesis. Intermediate K can be synthesized by condensationof intermediate I (obtained according to procedures described byBernatowicz et al., JOC, 57:2497 (1992)) and intermediate J (obtainedaccording to procedures described by Yamanaka et al., TetrahedronLetters, 37:1829 (1996)) in a solvent such as but not limited to DMF anda base such as but not limited to triethylamine.

EXAMPLES

The following Examples are offered as illustrative as a partial scopeand particular embodiments of the invention and are not meant to belimiting of the scope of the invention. Abbreviations and chemicalsymbols have their usual and customary meanings unless otherwiseindicated. Unless otherwise indicated, the compounds described hereinhave been prepared, isolated and characterized using the Schemes andother methods disclosed herein or may be prepared using the same.

As appropriate, reactions were conducted under an atmosphere of drynitrogen (or argon). For anhydrous reactions, DRISOLV® solvents from EMwere employed. For other reactions, reagent grade or HPLC grade solventswere utilized. Unless otherwise stated, all commercially obtainedreagents were used as received.

LC/MS measurements were obtained using a Shimadzu HPLC/Waters ZQ singlequadrupole mass spectrometer hybrid system. Data for the peak ofinterest are reported from positive-mode electrospray ionization. NMR(nuclear magnetic resonance) spectra were typically obtained on Brukeror JEOL 400 MHz and 500 MHz instruments in the indicated solvents. Allchemical shifts are reported in ppm from tetramethylsilane with thesolvent resonance as the internal standard. ¹H-NMR spectral data aretypically reported as follows: chemical shift, multiplicity (s=singlet,br s=broad singlet, d=doublet, dd=doublet of doublets, t=triplet,q=quartet, sep=septet, m=multiple, app=apparent), coupling constants(Hz), and integration.

One of skill in the art will recognize the standard abbreviationsutilized herein, throughout the specification. For ease of reference,the abbreviations include, but are not necessarily limited to:sat.=saturated, HPLC=high-performance liquid chromatography, AP=areapercent, KF=Karl-Fischer, RT=room temperature, mmol=millimoles, MS=massspectroscopy, CDCl₃=chloroform, NMP=N-methylpyrrolidone,TEA=triethylamine, IPA=isopropyl alcohol, TFA=trifluoroacetic acid,HCl=hydrochloric acid, EtOAc=ethyl acetate, CH₂Cl₂=methylene chloride,THF=tetrahydrofuran, DMF=N,N-dimethylformamide, SiO₂=silica dioxide,NaOH=sodium hydroxide, DMSO=dimethylsulfoxide, ° C.=degrees Celsius,g=gram or grams, mg=milligram or milligrams, mm=millimeter, mL (orml)=milliliter or milliliters, h=hour or hours, M=molar, N=normal,min=minute or minutes, MHz=megahertz, tlc=thin layer chromatography,v/v=volume to volume ratio, and ca.=about.

“α”, “β”, “R” and “S” are stereochemical designations familiar to thoseskilled in the art.

Preparation of Intermediate 15-Chloro-4-hydroxy-1-(4-(methylsulfonyl)phenyl)pyridin-2(1H)-one

To a 100 mL recovery flask was added 5-chloro-4-hydroxypyridin-2(1H)-one(291 mg, 2.0 mmol), copper (I) iodide (76 mg, 0.40 mmol),1,10-phenanthroline (72 mg, 0.40 mmol), and potassium carbonate (360 mg,6.0 mmol). The mixture was placed under vacuum for 2-4 minutes and thenvented to nitrogen. To this mixture was added DMSO (8 mL). Nitrogen wasbubbled subsurface for 10 seconds. The mixture was stirred at roomtemperature for 10 minutes under nitrogen.1-Bromo-4-(methylsulfonyl)benzene (470 mg, 2.0 mmol) was added andnitrogen was bubbled subsurface for 10 seconds. The reaction was cappedunder a nitrogen line and placed in a 140° C. oil bath for 13 hours.After cooling the reaction mixture to room temperature, the solids thatwere present were removed by filtration. The filtrate was added to 75 mLof ethyl acetate and was washed with 4×25 mL of 0.2 N aqueous HCl. Theorganic layer was dried with magnesium sulfate, filtered, andconcentrated to 2.0 g of an oily yellow powder. This material was heatedto reflux in 10 mL of methylene chloride at which point it was notcompletely soluble. The mixture was cooled to room temperature andfiltered. The solids were washed with 3×1 mL of methylene chloride anddried in vacuo. This provided 145 mg (24% yield) of Intermediate 1 as atan-yellow powder. ¹H NMR (DMSO-d₆, 500 MHz) δ 11.89 (1H, s), 7.93-8.14(3H, m), 7.70 (2H, d, J=8.8 Hz), 5.85 (1H, s), 3.28 (3H, s); MS (ESI)300.1 (M+1).

Preparation of Intermediate 21-(5-(Trifluoromethyl)pyrimidin-2-yl)piperidin-4-ol

Step A. Preparation of 4-hydroxypiperidine-1-carboximidamide, HCl

To a 1 liter round bottom flask was added piperidin-4-ol (13.11 g, 130mmol) and 1H-pyrazole-1-carboximidamide hydrochloride (19 g, 130 mmol).Vacuum was applied for 5 minutes and the mixture was vented to nitrogen.To this mixture was added DMF (65 mL). After stirring for 15 minutes,all of the solids had dissolved. Hunig's Base (22.6 mL, 130 mmol) wasadded over 2 minutes causing some cloudiness to develop. After 14 hours,250 g of ether was added to the pale yellow, cloudy reaction mixturecausing a pale yellow oil to settle out. This mixture was stirred for 5minutes. The nearly clear upper ether layer was decanted off and thisprocess repeated with two more ˜125 g washings of the residue withether. To the residue was added 100 mL of ethanol which dissolved mostof the oil. Ether (70 mL) was then added over 1-2 minutes causing amilky white appearance to the mixture and a pale yellow oil to form andsettle out to the bottom of the flask. The mixture was stirred for 1hour as the oil became an off-white crystalline solid. The conversion ofthe oil to the crystalline solid appeared to happen within 5-10 minutes.After stirring for 1 hour, the mixture was filtered and the off-whitecrystalline solid was washed with 3×25 mL of ether. After drying invacuo, the desired product (15.35 g, 66% yield) was obtained as anoff-white crystalline solid. ¹H NMR (DMSO-d₆, 500 MHz) δ 7.52 (4H, s),4.89 (1H, d, J=3.8 Hz), 3.68-3.84 (1H, m), 3.53-3.68 (2H, m), 3.09-3.29(2H, m), 1.59-1.86 (2H, m), 1.16-1.49 (2H, m); MS (ESI) 144.1 (M+1).

Step B. Preparation of1,1,5,5-tetramethyl-1,5-diaza-3-(trifluoromethyl)-1,3-pentadieniumChloride

To a 500 mL recovery flask under nitrogen was added3,3,3-trifluoropropanoic acid (10.83 mL, 123 mmol) and DMF (100 mL, 1286mmol) followed by phosphoryl trichloride (33.6 mL, 368 mmol) addeddropwise over 20 minutes. During this time the solution became warm andthen hot. An amber color developed while a mildly vigorous bubbling andgas evolution occurred. The mixture was placed in a 70° C. oil bathunder a nitrogen atmosphere with an open vent for 12 hours. Aftercooling the reaction mixture to room temperature, it was then placeddirectly onto a 95 mm id×150 mm silica gel column under 50% ethylacetate/hexane that had a head volume (amount of solvent sitting abovethe silica gel) of ˜500 mL of 50% ethyl acetate/hexane. The column wasthen eluted as follows:

Fraction Volume Solvent A 2.0 L 50% Ethyl acetate/hexane B 2.0 L Ethylacetate C 2.0 L THF D 2.0 L 50% Ethyl acetate/ethanol E-K 1.0 L Ethanol

Fractions E-J were combined and concentrated to give the desired product(21.0 g, 74%) as an oily yellow solid which was used with no furtherpurification in the next step. MS (ESI) 195.1 (M+1).

Step C. Preparation of Intermediate 2

To a 500 mL 3-neck round bottom flask under nitrogen was added1,1,5,5-tetramethyl-1,5-diaza-3-(trifluoromethyl)-1,3-pentadieniumchloride (21 g, 91 mmol) and DMF (175 mL) to produce a pale yellow,nearly clear solution. To this mixture was added4-hydroxypiperidine-1-carboximidamide hydrochloride (16.36 g, 91 mmol).Most of this solid dissolved. TEA (16.50 mL, 118 mmol) was added overone minute to produce a yellow-amber, cloudy mixture. A very smallamount of heat was generated as detected by a slight warming to theflask. After 22 hours at room temperature, the reaction mixture wasadded to 1000 mL of ethyl acetate and then washed with 2×500 mL of waterfollowed by 200 mL each of saturated aqueous sodium bicarbonate,saturated aqueous ammonium chloride, and brine. The organic layer wasdried with magnesium sulfate, filtered, and concentrated in vacuo to15.5 g of a tan solid. To this solid was added 15 mL of ethanol and 80mL of hexane. The mixture was heated to reflux at which point all of thesolids dissolved. The mixture was allowed to cool to room temperatureand a precipitate formed. The suspension was filtered and the solidswere washed with 4×25 mL of hexane and dried in vacuo. This providedIntermediate 2 (12.072 g, 74% yield) as a tan solid. ¹H NMR (CDCl₃, 500MHz) δ 8.48 (2H, s), 4.27-4.66 (2H, m), 4.07-4.08 (1H, m), 3.33-3.65(2H, m), 1.81-2.12 (2H, m), 1.41-1.74 (2H, m); MS (ESI) 248.2 (M+1).

Preparation of Intermediate 35-Chloro-4-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yloxy)pyridin-2(1H)-one

To a 100 mL recovery flask under nitrogen was added triphenylphosphine(1285 mg, 4.90 mmol), DMF (10 mL), and then (E)-diethyldiazene-1,2-dicarboxylate (0.67 mL, 4.20 mmol). The mixture was stirredat room temperature for 5 minutes at which point5-chloro-4-hydroxypyridin-2(1H)-one (509 mg, 3.50 mmol) was added. Afterstirring for an additional 5 minutes,1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-ol (1865 mg, 3.50 mmol)was added. The reaction was placed in a 100° C. oil bath under anitrogen atmosphere with a vent line for two hours. The clear amberreaction mixture was cooled to room temperature and added to 600 mL ofethyl acetate. After washing the ethyl acetate with water (2×200 mL),the solvent was removed in vacuo from the slightly cloudy, pale pinksolution to provide 3.06 g of a red, oily foam. This material waspurified using a 65 mm id×120 mm silica gel column and eluting asfollows:

Fraction Volume Solvent A 1 L 50% Ethyl acetate/hexane B 0.7 L Ethylacetate 1-15 125 mL 10% Methanol/ethyl acetate

Fractions 6-11 were combined and concentrated to provide Intermediate 3(579 mg, 44%) as a white powder. ¹H NMR (DMSO-d₆, 500 MHz) δ 11.41 (1H,br s), 8.71 (2H, s), 7.58 (1H, s), 6.05 (1H, s), 4.85 (1H, ddd, J=7.3,3.8, 3.7 Hz), 3.98-4.18 (2H, m), 3.66-3.91 (2H, m), 1.91-2.11 (2H, m),1.59-1.82 (2H, m); MS (ESI) 375.2 (M+H).

Preparation of Intermediate 4 1-(5-Chloropyrimidin-2-yl)piperidin-4-ol

To a one dram vial was added piperidin-4-ol (101 mg, 1 mmol),5-chloro-2-iodopyrimidine (240 mg, 1.000 mmol), and THF (1 mL) toproduce a suspension. To this mixture was added TEA (0.153 mL, 1.100mmol). The reaction was stirred at room temperature for 16 hours. Ethylacetate (7 mL) was added at that point and the mixture was washed withwater (4×2 mL). The organic layer was dried with magnesium sulfate,filtered, and concentrated in vacuo. The residue was purified by flashchromatography (silica gel, 0-40% ethyl acetate/hexane) to giveIntermediate 4 (185 mg, 87% yield) as white powder. ¹H NMR (CDCl₃, 500MHz) δ 8.22 (2H, s), 4.24-4.44 (2H, m), 3.83-4.04 (1H, m), 3.15-3.50(2H, m), 1.83-2.02 (2H, m), 1.40-1.60 (2H, m); MS (ESI) 214.2 (M+H).

Preparation of Intermediate 55-Chloro-1-(2-fluoro-4-(methylsulfonyl)phenyl)-4-(piperidin-4-yloxy)pyridin-2(1H)-one,Methanesulfonic Acid Salt

Step A: Preparation of Tert-butyl4-(5-chloro-2-oxo-1,2-dihydropyridin-4-yloxy)piperidine-1-carboxylate

A one liter round bottom flask was charged with5-chloro-4-hydroxypyridin-2(1H)-one (10 g, 68.7 mmol), t-butyl4-hydroxypiperidine-1-carboxylate (16.59 g, 82 mmol), triphenylphosphine(27.0 g, 103 mmol) and DMF (200 ml). This mixture was stirred for 40minutes to form a clear and homogeneous solution. The solution was thencooled to 0° C. and diisopropyl azodicarboxylate (16.23 mL, 82 mmol) wasadded drop-wise while maintaining the temperature below 20° C. duringthe addition. After the addition, the reaction mixture was allowed towarm to room temperature overnight. The reaction was then heated to 60°C. for 0.5 hours. After cooling the reaction mixture to roomtemperature, the DMF was distilled from the reaction under high vacuumat 50° C. to yield a brownish, viscous oil. The oil was dissolved in 300mL of chloroform and then was washed with dilute sodium bicarbonate (pH8-10) (3×50 mL) The chloroform layer was directly concentrated to afforda light yellow viscous oil, which was partitioned between 250 mL ofdiethyl ether and 70 mL of 1 N NaOH. The aqueous phase was extractedthoroughly with diethyl ether until LCMS showed no triphenylphosphineoxide or other impurities in the aqueous layer. The aqueous layer waspurged with nitrogen to remove residual ether and then acidified slowlywith 1 N HCl (˜70 mL) to pH 5 followed by cooling to 0° C. for 2 hours.The precipitates were collected by filtration, washed with ice water(2×20 mL), and air dried overnight. The light yellow solid was furthervacuum dried at 40° C. to a constant weight to yield t-butyl4-(5-chloro-2-oxo-1,2-dihydropyridin-4-yloxy)piperidine-1-carboxylate(13.2 g, 40.1 mmol, 58.4% yield) as a light yellow solid. ¹H-NMR (CDCl₃,400 MHz) δ 12.5 (br, s, 1H), 7.19 (s, 1H), 5.75 (s, 1H), 4.34-4.41 (m,1H), 3.40-3.48 (m, 2H), 3.26-3.37 (m, 2H), 1.71-1.83 (m, 2H), 1.60-1.71(m, 2H), 1.32 (s, 9H); MS m/e 329.3 (M+H⁺), 273.20 (M+H⁺-t-butyl).

Step B: Preparation of Tetrabutylammonium4-(1-(t-butoxycarbonyl)piperidin-4-yloxy)-5-chloropyridin-2-olate

A one liter round bottom flask was charged with t-butyl4-(5-chloro-2-oxo-1,2-dihydropyridin-4-yloxy)piperidine-1-carboxylate(69.2 g, 210 mmol) and pyridine (421 mL). The slurry was heated to 80°C. until all of the material dissolved to form a clear solution. At thistemperature, tetrabutylammonium hydroxide solution (152 mL, 232 mmol)was added. The mixture was concentrated in vacuo and the residual waterwas azeotropically removed with toluene (3×300 ml). The residue wasdried under high vacuum for 12 hours to give a wet solid which was useddirectly in the next reaction. ¹H-NMR (CDCl₃, 400 MHz) δ 7.65 (s, 1H),5.83 (s, 1H), 4.40-4.60 (m, 1H), 3.55-3.75 (m, 2H), 3.20-3.46 (m, 10H),1.72-2.0 (m, 4H); 1.55-1.72 (m, 8H), 1.30-1.55 (m, 17H), 1.0 (t, 12H,J=7.4 Hz); Anal. Calcd for C₃₁H₅₆ClN₃O₄.0.76H₂O: C, 63.76; H, 9.93; N,7.20; Cl, 6.07. Found: C, 63.76; H, 9.87; N, 7.09; Cl, 6.21.

Step C: Preparation of Tert-butyl4-(5-chloro-1-(2-fluoro-4-(methylsulfonyl)phenyl)-2-oxo-1,2-dihydropyridin-4-yloxy)piperidine-1-carboxylate

A two liter round bottom flask was charged with tetrabutylammonium4-(1-(t-butoxycarbonyl)piperidin-4-yloxy)-5-chloropyridin-2-olate (90 g,158 mmol), NMP (500 mL), and 1,2-difluoro-4-(methylsulfonyl)benzene(30.3 g, 158 mmol). The mixture was heated to 80° C. under nitrogen for12 hours. After cooling to room temperature, the reaction was dilutedwith ethyl acetate (500 mL) and distilled water (500 mL). The organiclayer was separated, dried over anhydrous sodium sulfate, filtered andconcentrated in vacuo. To the residue was added 500 mL of 20% ethylacetate in diethyl ether and the mixture was stirred for 12 hours atroom temperature. The slurry was then cooled to 4° C. and stirring wascontinued for additional 1 hour. The solid was collected by filtrationand dried under vacuum for 4 hours at 45° C. to yield t-butyl4-(5-chloro-1-(2-fluoro-4-(methylsulfonyl)phenyl)-2-oxo-1,2-dihydropyridin-4-yloxy)piperidine-1-carboxylate(58 g, 70% yield) as a white solid. ¹H-NMR (CDCl₃, 400 MHz) δ 7.85-7.89(m, 1H), 7.61-7.64 (m, 1H), 7.32 (s, 1H), 6.02 (s, 1H), 4.57-4.63 (m,1H), 3.59-3.69 (m, 2H), 3.44-3.55 (m, 2H), 3.11 (s, 3H), 1.83-2.05 (m,4H), 1.48 (s, 9H); MS m/e 501.2 (M+H⁺).

Step D: Preparation of Intermediate 5

A two liter round bottom flask was charged with t-butyl4-(5-chloro-1-(2-fluoro-4-(methylsulfonyl)phenyl)-2-oxo-1,2-dihydropyridin-4-yloxy)piperidine-1-carboxylate(98 g, 196 mmol) and acetonitrile (489 mL) and slurried for 15 minutes.Methanesulfonic acid (25.4 mL, 391 mmol) was then added and the reactionmixture was heated to 50° C. for 2 hours. While maintaining the reactionat 50° C., 500 mL of ethyl acetate was added slowly via an additionalfunnel. After the addition was completed, the suspension was cooled toroom temperature overnight and then further cooled to 0° C. for 2 hours.The product was collected by filtration, thoroughly rinsed with ethylacetate, and dried under vacuum overnight to yield Intermediate 5 (92 g,92% yield) as a gray solid. ¹H-NMR (DMSO-d₆, 400 MHz) δ 8.52 (br, 1H),8.45 (br, 1H), 8.14 (s, 1H), 8.02-8.05 (m, 1H), 7.91-7.93 (m, 1H),7.83-7.86 (m, 1H), 6.32 (s, 1H), 4.82-4.90 (m, 1H), 3.36 (s, 3H),3.09-3.30 (m, 4H), 2.34 (s, 3H), 2.10-2.21 (m, 2H), 1.82-1.92 (m, 2H);MS m/e 401.1 (M+H⁺).

Preparation of Intermediate 65-Chloro-4-(1-(5-chloropyrimidin-2-yl)piperidin-4-yloxy)pyridin-2(1H)-one

To a 200 mL recovery flask was added triphenylphosphine (7.34 g, 28.0mmol) and DMF (40 mL) to produce a nearly complete solution with 2-3minutes of stirring. To this mixture was added (E)-diethyldiazene-1,2-dicarboxylate (3.80 mL, 24.00 mmol). After stirring at roomtemperature for 5 minutes, 5-chloro-4-hydroxypyridin-2(1H)-one(Gimeracil) (5.82 g, 40.0 mmol) was added. After stirring at roomtemperature for 5 minutes, 1-(5-chloropyrimidin-2-yl)piperidin-4-ol(4.27 g, 20 mmol) was added. The reaction mixture was placed under anitrogen line with a vent and placed in a 100° C. oil bath for 115minutes. After cooling to room temperature, the clear brown reactionmixture was added to 1000 mL of ether with stirring which resulted inthe formation of a tan-pink oily precipitate. To this mixture was added500 mL of hexane. The mixture was stirred for 5 minutes and then allowedto settle for 10 minutes. The mixture was poured through a mediumporosity funnel. The tan-pink solids that were retained were washed with100 mL of ether/hexane (1/2 ratio) and dried in vacuo to provide 5.06 gof tan-pink solids. The clear, nearly colorless filtrate wasconcentrated to 54 g of a clear pale amber liquid. This material wasdissolved in 500 mL of ethyl acetate and washed with 3×50 mL of water.The ethyl acetate solution was dried with magnesium sulfate, filtered,and concentrated to 20.3 g of tan solids. This was combined with the5.06 g of tan-pink solids from above and purified on a 60 mm id×160 mmsilica gel column eluting as follows:

Fraction Volume Solvent A-C 0.4 L each Methylene chloride D 1 L 1%Methanol/methylene chloride E 1 L 2% Methanol/methylene chloride F 1 L3% Methanol/methylene chloride G 0.4 L 5% Methanol/methylene chloride H0.2 mL 5% Methanol/methylene chloride  1-14 125 mL 5% Methanol/methylenechloride 15-30 125 mL 25% Methanol/methylene chloride

Fractions G, H, and 1-5 were combined and concentrated to provide 2.89 g(40% yield) of solid Intermediate 6. ¹H NMR (DMSO-d₆, 500 MHz) δ 11.39(1H, br s), 8.42 (2H, s), 7.57 (1H, s), 6.03 (1H, s), 4.66-4.91 (1H, m),3.87-4.14 (2H, m), 3.51-3.81 (2H, m), 1.85-2.05 (2H, m), 1.48-1.75 (2H,m); MS (ESI) 341.2 (M+H).

Preparation of Intermediate 75-Chloro-1-(4-(ethylsulfonyl)phenyl)-4-hydroxypyridin-2(1H)-one

To a 100 mL recovery flask was added 5-chloro-4-hydroxypyridin-2(1H)-one(470 mg, 3.23 mmol), copper (I) iodide (123 mg, 0.646 mmol),1,10-phenanthroline (116 mg, 0.646 mmol), potassium carbonate (582 mg,9.69 mmol), and DMSO (10 mL). Nitrogen was bubbled subsurface for 10seconds and the mixture capped under nitrogen. After stirring for 5minutes, 1-bromo-4-(ethylsulfonyl)benzene (805 mg, 3.23 mmol) was addedand nitrogen was again bubbled subsurface for 10 seconds. The mixturewas placed under nitrogen with a vent and placed in a 140° C. oil bathfor 19 hours. After cooling to room temperature, the brown cloudyreaction mixture was added to 200 mL of ethyl acetate and washed with4×50 mL of 0.2 N HCl. The organic layer was dried with magnesiumsulfate, filtered, and concentrated in vacuo to ˜0.7 g of an oily,yellow-tan solid. This material was slurried in 5 mL of methylenechloride at reflux which resulted in the material becoming a yellow-tancrystalline powder. After cooling to room temperature, the suspensionwas filtered, washed with 2×1 mL of methylene chloride, and dried invacuo to provide 375 mg (37% yield) of Intermediate 7 as a yellow-tanpowder. ¹H NMR (DMSO-d₆, 500 MHz) δ 11.89 (1H, s), 7.85-8.09 (3H, m),7.71 (2H, d, J=8.2 Hz), 5.85 (1H, s), 3.08-3.54 (2H, m), 1.14 (3H, t,J=7.1 Hz); MS (ESI) 314.1 (M+1).

Preparation of Intermediate 8 4-(Ethylsulfonyl)-1,2-difluorobenzene

To thick-walled reaction pressure tube was added3,4-difluorobenzenethiol (1500 mg, 10.26 mmol), iodoethane (1.095 mL,13.34 mmol), acetonitrile (20 mL), and triethylamine (1.860 mL, 13.34mmol). The vessel was capped and heated at 80° C. for 2 hours. Aftercooling to room temperature, the reaction mixture was concentrated.Methylene chloride was added and the mixture was washed with water threetimes. The organic layer was concentrated to provide crude4-(ethylthio)-1,2-difluorobenzene which was used without furtherpurification. This material was combined with 2-propanol (20 mL) andwater (10 mL). To the mixture was added OXONE® (8388 mg, 13.7 mmol).After stirring at room temperature overnight, the reaction mixture wasevaporated in vacuo and the residue was extracted with ethyl acetate.The ethyl acetate was washed with water three times followed bysaturated aqueous sodium bicarbonate and then brine. The organic layerwas dried with sodium sulfate, filtered, and concentrated. The resultingresidue was purified by flash chromatography (silica gel, 0-100% ethylacetate/hexane) to give Intermediate 8 (2 g, 99% yield) as white solid.¹H NMR (CDCl₃, 500 MHz) δ 7.67-7.82 (m, 2H), 7.38 (dd, J=16.22, 9.07 Hz,1H), 3.13 (q, J=7.70 Hz, 2H), 1.25-1.32 (m, 3H); MS (ESI) 207.1 (M+H).

Preparation of Intermediate 9 1-(Ethylsulfonyl)-2,4-difluorobenzene

To thick-walled, reaction pressure tube was added2,4-difluorobenzenethiol (1500 mg, 10.26 mmol), iodoethane (1.095 mL,13.34 mmol), acetonitrile (20 mL), and triethylamine (1.860 mL, 13.34mmol). The vessel was capped and heated at 80° C. for 2 hours. Aftercooling to room temperature, the reaction mixture was concentrated invacuo. Methylene chloride was added and the mixture was washed withwater three times. The organic layer was concentrated to provide crude4-(ethylthio)-1,3-difluorobenzene which was used without furtherpurification. To this material (1700 mg, 9.76 mmol) in acetic acid (10mL) was added hydrogen peroxide (30% in H₂O, 4.7 mL, 48.8 mmol). Themixture was refluxed for 2 hours. After cooling to room temperature, thereaction mixture was added to methylene chloride and washed with waterthree times. The organic layer was dried with sodium sulfate, filtered,and concentrated. The resulting residue was purified by flashchromatography (silica gel, 0-100% ethyl acetate/hexane) to give1-(ethylsulfinyl)-2,4-difluorobenzene (1.2 g, 6.31 mmol) as white oil.¹H NMR (CDCl₃, 500 MHz) δ 7.69-7.86 (m, 1H), 7.03-7.17 (m, 1H),6.80-6.94 (m, 1H), 3.05 (dd, J=13.75, 7.15 Hz, 1H), 2.83 (dd, J=13.75,7.15 Hz, 1H), 1.22 (t, J=7.42 Hz, 3H); MS (ESI) 191.1 (M+H). To asolution of 1-(ethylsulfinyl)-2,4-difluorobenzene (1100 mg, 5.78 mmol)in 2-propanol (10 mL) was added water (10 mL) and OXONE® (4622 mg, 7.52mmol). The mixture was stirred at room temperature for 16 hours. Thereaction mixture was then filtered and the filtrate was concentrated.The resulting crude material was dissolved in ethyl acetate and waswashed with saturated aqueous sodium chloride twice. The organic layerwas dried with sodium sulfate, filtered, and concentrated. The residueobtained was then purified by flash chromatography (silica gel, 0-100%ethyl acetate/hexane) to give Intermediate 9 (600 mg, 50% yield) as awhite oil. ¹H NMR (CDCl₃, 500 MHz) δ 7.90-8.02 (1H, m), 6.90-7.12 (2H,m), 3.30 (2H, q, J=7.3 Hz), 1.30 (3H, t, J=7.4 Hz); MS (ESI) 207.1(M+H).

Example 15-Chloro-1-(4-(methylsulfonyl)phenyl)-4-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yloxy)pyridin-2(1H)-one

To a 200 mL recovery flask under nitrogen was added Intermediate 1(2.997 g, 10.00 mmol), Intermediate 2 (2.72 g, 11.00 mmol),triphenylphosphine (3.41 g, 13.00 mmol), and THF (5 mL) to produce atan-amber suspension. To this mixture was added (E)-diethyldiazene-1,2-dicarboxylate (2.055 mL, 12.98 mmol) over 1 minute. A smallamount of heat was generated and the color became dark brown. Within twominutes, most of the solids had dissolved. By 10 minutes, a thick,tan-brown precipitate had formed. After 15 minutes, 100 mL of ether wasadded. The thick tan suspension was stirred for 5 minutes, filtered, andthe solids washed with 4×15 mL of ether to give 4.19 g of a tan powder.This material was loaded onto a 70 mm id×110 mm silica gel column as asuspension and eluted as follows:

Fraction Volume Solvent A 1.8 L 75% Ethyl acetate/hexane B 0.7 L 100%Ethyl acetate 1-2 125 mL 100% Ethyl acetate 3-15 125 mL 5%Methanol/ethyl acetate

Fractions 1-8 were concentrated to 4.3 g of a damp, pale tan solid. Thismaterial was suspended in 50 mL of ethanol and heated to reflux, atwhich point only partial solubilization occurred. The suspension wasthen allowed to cool to room temperature and was filtered. The solidswere washed with 2×10 mL of ethanol and 2×10 mL of hexane followed bydrying overnight under high vacuum. This provided 2.72 g (52% yield) ofExample 1 as an off-white crystalline solid. ¹H NMR (CDCl₃, 400 MHz) δ1.85-2.24 (m, 18H) 3.10 (s, 14H) 3.92-4.23 (m, 18H) 4.63-4.85 (m, 5H)6.08 (s, 5H) 7.45 (s, 4H) 7.64 (d, J=8.79 Hz, 9H) 8.10 (d, J=8.35 Hz,9H) 8.51 (s, 8H); MS (ESI) 529.2 (M+1).

Example 25-Chloro-1-(2-fluoro-4-(methylsulfonyl)phenyl)-4-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yloxy)pyridin-2(1H)-one

To a 4 mL vial was added a 60% oil dispersion of sodium hydride (53 mg,1.33 mmol), DMF (10 mL), and Intermediate 3 (250 mg, 0.67 mmol). Themixture was stirred at room temperature for 30 minutes and then1,2-difluoro-4-(methylsulfonyl)benzene (192 mg, 1.00 mmol) was added.The mixture was heated at 100° C. for 12 hours. After cooling to roomtemperature, the reaction mixture was diluted with ethyl acetate (40 mL)and washed with water three times. The organic layer was collected,dried over sodium sulfate, and filtered. The residue obtained waspurified by flash chromatography (silica gel, 0-100% ethylacetate/hexane) to give Example 2 (139 mg, 37% yield) as a yellow solid.¹H NMR (DMSO-d₆, 500 MHz) δ 8.72 (2H, s), 8.11 (1H, s), 7.97-8.06 (1H,m), 7.78-7.95 (2H, m), 6.31 (1H, s), 4.90-5.01 (1H, m), 4.06-4.22 (2H,m), 3.74-3.89 (2H, m), 3.36 (3H, s), 1.98-2.16 (2H, m), 1.62-1.83 (2H,m); MS (ESI) 547.1 (M+H).

Example 35-Chloro-1-(3-fluoro-4-(methylsulfonyl)phenyl)-4-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yloxy)pyridin-2(1H)-one

A mixture of a 60% oil dispersion of sodium hydride (34 mg, 0.87 mmol),Intermediate 3 (216 mg, 0.58 mmol), and DMF (10 mL) was stirred at roomtemperature for 30 minutes. 2,4-Difluoro-1-(methylsulfonyl)benzene (144mg, 0.75 mmol) was added and the mixture was heated at 100° C. for 16hours. After cooling to room temperature, the crude mixture was dilutedwith ethyl acetate and washed with water three times. The organic layerwas dried with sodium sulfate, filtered, and concentrated. The residueobtained was purified by flash chromatography (silica gel, 0-100% ethylacetate/hexane) to give Example 3 (80 mg, 25% yield) as yellow solid. ¹HNMR (500 MHz, CDCl₃) δ 8.53 (s, 2H), 8.10 (t, J=7.70 Hz, 1H), 7.32-7.49(m, 3H), 6.06 (s, 1H), 4.67-4.79 (m, 1H), 3.99-4.19 (m, 4H), 3.25 (s,3H), 1.91-2.16 (m, 4H); MS (ESI) 547.2 (M+H).

Example 45-Chloro-4-(1-(5-chloropyrimidin-2-yl)piperidin-4-yloxy)-1-(4-(methylsulfonyl)phenyl)pyridin-2(1H)-one

To a 2 dram vial was added Intermediate 1 (276 mg, 0.92 mmol),Intermediate 4 (206 mg, 0.96 mmol) and triphenylphosphine (314 mg, 1.20mmol) followed by THF (3 mL) to produce a thin suspension. To thismixture was added (E)-diethyl diazene-1,2-dicarboxylate (0.19 mL, 1.20mmol) over ten seconds. All solids appeared to have dissolved althoughthe reaction was a turbid yellow-brown mixture. Approximately 3.5minutes after the addition of (E)-diethyl diazene-1,2-dicarboxylate, athick tan-yellow precipitate had formed. After 48 minutes from theaddition of (E)-diethyl diazene-1,2-dicarboxylate, ether (5 mL) wasadded. The mixture was stirred for 5 minutes, filtered, and the solidswere washed with 3×2 mL of ether. The tan powder obtained after dryingin vacuo (330 mg) was suspended in 4 mL of ethanol at reflux. Much ofthe solids did not dissolve. The mixture was cooled to room temperature.The solids were isolated by filtration and were washed with 2×1 mL ofethanol followed by 2×1 mL of hexane. Drying in vacuo gave Example 4(256 mg, 54%) as a pale tan powder. ¹H NMR (CDCl₃, 500 MHz) δ 8.25 (2H,s), 8.09 (2H, d, J=8.3 Hz), 7.63 (2H, d, J=8.3 Hz), 7.44 (1H, s), 6.07(1H, s), 4.58-4.79 (1H, m), 3.96-4.10 (2H, m), 3.83-3.96 (2H, m),1.83-2.15 (4H, m); MS (ESI) 495.0 (M+H).

Example 55-Chloro-4-(1-(5-chloropyrimidin-2-yl)piperidin-4-yloxy)-1-(2-fluoro-4-(methylsulfonyl)phenyl)pyridin-2(1H)-one

A two liter round bottom flask was charged with Intermediate 5 (100 g,201 mmol), NMP (501 mL), 2,5-dichloropyrimidine (30.0 g, 201 mmol), andN,N-diisopropylethylamine (70.3 mL, 402 mmol). This mixture was heatedat 70° C. for 6 hours and then cooled to room temperature. The reactionmixture was diluted with dichloromethane (500 mL) and then washed withsaturated aqueous sodium bicarbonate (500 mL). The organic layer wasseparated and concentrated in vacuo at room temperature to obtain acrude oil (˜400 g). The oil was transferred to two liter 3-necked flaskwith minimal NMP (50 mL) rinse and heated to 80° C. To this mixture wasadded 500 mL of ethanol slowly via an additional funnel while keepinginternal temperature at 80° C. After the addition of 150 mL ethanol,precipitates gradually formed. The suspension was stirred at 80° C. for40 minutes and then cooled to room temperature overnight. The suspensionwas further slowly cooled to 0° C. and then kept at 0° C. for 1.5 hours.After filtration, the filtering cake was washed with 4° C. ethanol(2×200 mL). The filtering cake was dried under vacuum for 2 hours andthen vacuum dried overnight at 45° C. to yield5-chloro-4-(1-(5-chloropyrimidin-2-yl)piperidin-4-yloxy)-1-(2-fluoro-4-(methylsulfonyl)phenyl)pyridin-2(1H)-one(68.9 g, 67%) as a white solid. ¹H-NMR (CDCl₃, 400 MHz) δ 8.28 (s, 2H),7.82-8.00 (m, 2H), 7.59-7.72 (m, 1H), 7.35 (s, 1H), 6.09 (s, 1H),4.65-4.73 (m, 1H), 3.89-4.12 (m, 4H), 3.13 (s, 3H), 1.95-2.17 (m, 4H);MS m/e 513.2 (M+H⁺); Anal. Calcd for C₂₁H₉N₄O₄Cl₂FS: C, 49.03; H, 3.78;N, 10.86; S, 6.18; Cl, 13.89; F, 3.66. Found: C, 49.17; H, 3.67; N,10.86, S, 6.15, Cl, 14.02, F, 3.88.

Example 65-Chloro-4-(1-(5-chloropyrimidin-2-yl)piperidin-4-yloxy)-1-(3-fluoro-4-(methylsulfonyl)phenyl)pyridin-2(1H)-one

Step A. Preparation of Tert-butyl4-(5-chloro-1-(3-fluoro-4-(methylsulfonyl)phenyl)-2-oxo-1,2-dihydropyridin-4-yloxy)piperidine-1-carboxylate

A suspension of tert-butyl4-(5-chloro-2-oxo-1,2-dihydropyridin-4-yloxy)piperidine-1-carboxylate(400 mg, 1.22 mmol), sodium hydride (60 wt % in mineral oil, 58 mg, 1.5mmol) and DMF (8 mL) was purged with argon and then stirred at roomtemperature for 20 minutes. To the reaction was added2,4-difluoro-1-(methylsulfonyl)benzene (351 mg, 1.83 mmol) and thenheated at 130° C. for 1 hour. The resulting mixture was quenched withH₂O and extracted with EtOAc. The organic layer was concentrated invacuo to a brown oil. The oil was purified by flash chromatography(SiO₂, 0 to 100% EtOAc in CH₂Cl₂) to yield 321 mg of the desired productas an off-white solid. ¹H NMR (400 MHz, CDCl₃) δ ppm 8.07-8.14 (m, 1H)7.35-7.47 (m, 3H) 6.01 (s, 1H) 4.57-4.64 (m, 1H) 3.60-3.69 (m, 2H)3.44-3.55 (m, 2H) 3.26 (s, 3H) 1.93-2.03 (m, 2H) 1.83-1.93 (m, 2H) 1.49(s, 9H). MS (ESI) 445 (M−56+H).

Step B. Preparation of5-chloro-1-(3-fluoro-4-(methylsulfonyl)phenyl)-4-(piperidin-4-yloxy)pyridin-2(1H)-oneHydrochloride Salt

A mixture of tert-butyl4-(5-chloro-1-(3-fluoro-4-(methylsulfonyl)phenyl)-2-oxo-1,2-dihydropyridin-4-yloxy)piperidine-1-carboxylate(300 mg, 0.599 mmol) and hydrogen chloride (37% in H₂O, 5 mL) wasstirred for 15 min and then concentrated in vacuo to yield 261 mg of thedesired product as an off-white solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm8.88 (br s, 2H) 8.11 (s, 1H) 7.97 (t, J=8.16 Hz, 1H) 7.78 (dd, J=10.92,1.88 Hz, 1H) 7.57 (dd, J=8.28, 1.76 Hz, 1H) 6.30 (s, 1H) 4.80-491 (m,1H) 3.39 (s, 3H) 3.05-3.26 (m, 4H) 2.10-2.20 (m, 2H) 1.85-1.98 (m, 2H).MS (ESI) 401 (M+H).

Step C Example 6

A suspension of5-chloro-1-(3-fluoro-4-(methylsulfonyl)phenyl)-4-(piperidin-4-yloxy)pyridin-2(1H)-onehydrochloride salt (260 mg, 0.595 mmol), potassium carbonate (205 mg,1.49 mmol) and 5-chloro-2-iodopyrimidine (172 mg, 0.713 mmol) in dryDMSO (5 mL) was stirred overnight at room temperature. The reactionmixture was diluted with H₂O and extracted with EtOAc. The organic layerwas concentrated in vacuo to a light yellow oil. The oil was purified byflash chromatography (SiO₂, 0 to 100% EtOAc in CH₂Cl₂) to yield 228 mgof Example 6 as a white solid. ¹H NMR (400 MHz, CDCl₃) δ ppm 8.25 (s,2H) 8.07-8.16 (m, 1H) 7.35-7.49 (m, 3H) 6.06 (s, 1H) 4.66-4.73 (m, 1H)3.97-4.06 (m, 2H) 3.86-3.96 (m, 2H) 3.26 (s, 3H) 2.01-2.11 (m, 2H)1.91-2.01 (m, 2H). MS (ESI) 513 (M+H).

Alternatively, Example 6 may be prepared as follows:

Step A. Preparation of Tert-butyl4-(5-chloro-1-(3-fluoro-4-(methylsulfonyl)phenyl)-2-oxo-1,2-dihydropyridin-4-yloxy)piperidine-1-carboxylate

A suspension of tert-butyl4-(5-chloro-2-oxo-1,2-dihydropyridin-4-yloxy)piperidine-1-carboxylate(400 mg, 1.22 mmol), sodium hydride (60% wt in mineral oil, 58 mg, 1.5mmol) and DMF (8 mL) was purged with Argon and then stirred at roomtemperature for 20 min. To the reaction was added2,4-difluoro-1-(methylsulfonyl)benzene (351 mg, 1.83 mmol) and thenheated at 130° C. for 1 hour. The resulting mixture was quenched withH₂O and extracted with EtOAc. The organic layer was concentrated invacuo to a brown oil. The oil was purified by flash chromatography(SiO₂, 0 to 100% EtOAc in CH₂Cl₂) to yield 321 mg of the desired productas an off-white solid. ¹H NMR (400 MHz, CDCl₃) δ ppm 8.07-8.14 (m, 1H)7.35-7.47 (m, 3H) 6.01 (s, 1H) 4.57-4.64 (m, 1H) 3.60-3.69 (m, 2H)3.44-3.55 (m, 2H) 3.26 (s, 3H) 1.93-2.03 (m, 2H) 1.83-1.93 (m, 2H) 1.49(s, 9H). MS (ESI) 445 (M−56+H).

Step B. Preparation of5-chloro-1-(3-fluoro-4-(methylsulfonyl)phenyl)-4-(piperidin-4-yloxy)pyridin-2(1H)-oneHydrochloric Acid Salt

A mixture of tert-butyl4-(5-chloro-1-(3-fluoro-4-(methylsulfonyl)phenyl)-2-oxo-1,2-dihydropyridin-4-yloxy)piperidine-1-carboxylate(300 mg, 0.599 mmol) and hydrogen chloride (37% in H₂O, 5 mL) wasstirred for 15 min and then concentrated in vacuo to yield 261 mg of thedesired product as an off-white solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm8.88 (br. s., 2H) 8.11 (s, 1H) 7.97 (t, J=8.16 Hz, 1H) 7.78 (dd,J=10.92, 1.88 Hz, 1H) 7.57 (dd, J=8.28, 1.76 Hz, 1H) 6.30 (s, 1H)4.80-4.91 (m, 1H) 3.39 (s, 3H) 3.05-3.26 (m, 4H) 2.10-2.20 (m, 2H)1.85-1.98 (m, 2H). MS (ESI) 401 (M+H).

Step C Example 6

A suspension of5-chloro-1-(3-fluoro-4-(methylsulfonyl)phenyl)-4-(piperidin-4-yloxy)pyridin-2(1H)-onehydrochloric acid salt (260 mg, 0.595 mmol), potassium carbonate (205mg, 1.49 mmol) and 5-chloro-2-iodopyrimidine (172 mg, 0.713 mmol) in dryDMSO (5 mL) was stirred overnight at room temperature. The reactionmixture was diluted with H₂O and extracted with EtOAc. The organic layerwas concentrated in vacuo to a light yellow oil. The oil was purified byflash chromatography (SiO₂, 0 to 100% EtOAc in CH₂Cl₂) to yield 228 mgof Example 6 as a white solid. ¹H NMR (400 MHz, CDCl₃) δ ppm 8.25 (s,2H) 8.07-8.16 (m, 1H) 7.35-7.49 (m, 3H) 6.06 (s, 1H) 4.66-4.73 (m, 1H)3.97-4.06 (m, 2H) 3.86-3.96 (m, 2H) 3.26 (s, 3H) 2.01-2.11 (m, 2H)1.91-2.01 (m, 2H). MS (ESI) 513 (M+H).

Example 75-Chloro-1-(4-(ethylsulfonyl)phenyl)-4-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yloxy)pyridin-2(1H)-one

To a mixture of Intermediate 7 (100 mg, 0.319 mmol), Intermediate 2 (87mg, 0.351 mmol), and triphenylphosphine (109 mg, 0.414 mmol) was addedTHF (1 mL) to give a tan-brown suspension. (E)-Diethyldiazene-1,2-dicarboxylate (0.066 mL, 0.414 mmol) was added and allsolids dissolved within 10 seconds. By 3 minutes from the addition ofthe (E)-diethyl diazene-1,2-dicarboxylate, a thick tan precipitate hadformed. After 10 minutes, 3 mL of ether was added. The suspension wasstirred for one minute, filtered, and washed with 3×1 mL ether. Thesolids were dried in vacuo to give 121 mg of a tan powder. To this solidwas added 2 mL of ethanol and the mixture was heated briefly at refluxat which point not all was soluble. After allowing this mixture to coolto room temperature, it was filtered and the solids were washed with2×0.5 mL of ethanol and 2×1 mL of hexane. The solids were dried in vacuoto yield 98 mg (57% yield) of Example 7 as an off-white powder. ¹H NMR(CDCl₃, 500 MHz) δ 8.51 (2H, s), 8.05 (2H, d, J=8.2 Hz), 7.63 (2H, d,J=8.8 Hz), 7.45 (1H, s), 6.07 (1H, s), 4.74 (1H, br. s.), 3.94-4.21 (4H,m), 3.16 (2H, q, J=7.1 Hz), 1.91-2.17 (4H, m), 1.35 (3H, t, J=7.4 Hz);MS (ESI) 543.1 (M+1).

Example 85-Chloro-1-(4-(ethylsulfonyl)-2-fluorophenyl)-4-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yloxy)pyridin-2(1H)-one

To a 250 mL round bottom flask was added Intermediate 3 (3.00 g, 8.01mmol) and DMF (60 mL) to produce a suspension. To this mixture was addeda 60% oil dispersion of sodium hydride (432 mg, 10.81 mmol). The mixturewas stirred for 30 minutes under an atmosphere of nitrogen during whichtime it became a clear yellow solution. To this solution was addedIntermediate 8 (1816 mg, 8.81 mmol). The mixture was then heated undernitrogen at 120° C. for 12 hours. After cooling to room temperature, thereaction mixture was added to ethyl acetate (600 mL) and washed withwater (4×200 mL). The ethyl acetate was dried with sodium sulfate,filtered, and concentrated to a yellow oil. This material was dissolvedin methylene chloride and purified by flash chromatography (silica gel,0-100% ethyl acetate/hexane) to give Example 8 (2.85 g, 62% yield) as awhite solid. A number of samples of this material, prepared in the sameway, were combined to give 4.0 g of material. The 4.0 g of material wasadded to ethanol (140 mL) and heated to reflux at which point only avery small amount of insoluble matter remained. The hot solution wasfiltered through a medium porosity sinctered glass funnel and the funnelrinsed with 10 mL of hot ethanol. The hot filtrate began to crystallizeimmediately. Upon heating the filtrate to reflux, most of the solidsdissolved. This mixture was allowed to cool to room temperature and thenstirred for two hours. The mixture was filtered, washed with roomtemperature ethanol (2×15 mL) and hexane (25 mL), and the solids weredried in vacuo. This yielded 3.18 g of an off-white solid. The mainportion of this material (3.17 g) was heated to reflux in ethanol (130mL), allowed to cool to room temperature, and then stirred overnight.The mixture was filtered, washed with room temperature ethanol (2×15 mL)and hexane (25 mL), and the solids were dried in vacuo. Thisrecrystallization provided 2.91 g of an off-white, fine powder. ¹H NMR(CDCl₃, 500 MHz) δ 8.51 (2H, s), 7.84 (2H, dd, J=7.1, 4.9 Hz), 7.57-7.70(1H, m), 7.34 (1H, s), 6.07 (1H, s), 4.74 (1H, t, J=3.3 Hz), 3.96-4.19(4H, m), 3.18 (2H, q, J=7.1 Hz), 1.91-2.16 (4H, m), 1.37 (3H, t, J=7.4Hz); MS (ESI) 561.2 (M+H).

Example 95-Chloro-1-(4-(ethylsulfonyl)-3-fluorophenyl)-4-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yloxy)pyridin-2(1H)-one

A mixture of Intermediate 3 (91 mg, 0.242 mmol) and a 60% oil dispersionof sodium hydride (10.67 mg, 0.267 mmol) in DMF (1.5 mL) was stirred for20 minutes. Intermediate 9 (50 mg, 0.242 mmol) was added and the mixturewas heated at 100° C. for 10 hours. After cooling to room temperature,water (3 mL) was added to the reaction mixture. This mixture was thenextracted with ethyl acetate. The extract was concentrated and theresulting residue was purified by flash chromatography (silica gel,0-100% ethyl acetate/hexane) to give Example 9 (24 mg, 17% yield) as awhite solid. ¹H NMR (CDCl₃, 500 MHz) δ 8.50 (s, 2H), 8.07 (t, J=7.97 Hz,1H), 7.32-7.49 (m, 3H), 6.05 (s, 1H), 4.67-4.79 (m, 1H), 3.96-4.14 (m,4H), 3.35 (q, J=7.15 Hz, 2H), 1.93-2.12 (m, 4H), 1.36 (t, 3H); MS (ESI)561.1 (M+H).

Example 105-Chloro-4-(1-(5-chloropyrimidin-2-yl)piperidin-4-yloxy)-1-(4-(ethylsulfonyl)phenyl)pyridin-2(1H)-one

To a suspension of Intermediate 7 (50 mg, 0.16 mmol), Intermediate 4 (41mg, 0.19 mmol), and triphenylphosphine (50.2 mg, 0.19 mmol) in THF (1.5mL) was added (E)-diethyl diazene-1,2-dicarboxylate (0.030 mL, 0.19mmol). After stirring at room temperature for two hours, ether (2 mL)was added to the reaction mixture. A white precipitate formed and wascollected by filtration to provide Example 10 (33 mg, 40% yield) as awhite solid. ¹H NMR (CDCl₃, 500 MHz) δ 8.27-8.40 (m, 2H), 8.00-8.11 (m,2H), 7.62 (d, J=8.80 Hz, 2H), 7.38-7.50 (m, 1H), 6.07 (s, 1H), 4.65-4.80(m, 1H), 3.87-4.33 (m, 4H), 3.05-3.23 (m, 2H), 1.97-2.15 (m, 4H), 1.34(t, J=7.42 Hz, 3H); MS (ESI) 509.1 (M+H).

Example 115-Chloro-4-(1-(5-chloropyrimidin-2-yl)piperidin-4-yloxy)-1-(4-(ethylsulfonyl)-2-fluorophenyl)pyridin-2(1H)-one

A mixture of Intermediate 6 (30 mg, 0.09 mmol) and a 60% oil dispersionof sodium hydride (7 mg, 0.18 mmol) in DMF (0.4 mL) was stirred for 20minutes. Intermediate 8 (27 mg, 0.132 mmol) was added and the reactionwas heated at 110° C. for 12 hours. After cooling to room temperature,water was added to the reaction mixture followed by extraction withethyl acetate twice. The combined extracts were concentrated. Theresidue was dissolved in methanol and purified by preparative HPLC (C₁₈column; 40-100% methanol in water containing 0.05% trifluoroacetic acid)to give Example 11 (8 mg, 16% yield) as a white solid. ¹H NMR (CDCl₃,500 MHz) δ 8.25 (s, 2H), 7.83 (s, 2H), 7.55-7.68 (m, 1H), 7.32 (s, 1H),6.07 (s, 1H), 4.61-4.74 (m, 1H), 3.80-4.07 (m, 4H), 3.17 (d, J=7.70 Hz,2H), 1.87-2.11 (m, 4H), 1.36 (t, 3H); MS (ESI) 527.0 (M+1).

Example 125-Chloro-4-(1-(5-chloropyrimidin-2-yl)piperidin-4-yloxy)-1-(4-(ethylsulfonyl)-3-fluorophenyl)pyridin-2(1H)-one

To a suspension of Intermediate 6 (50 mg, 0.13 mmol) in DMF in a 4 mLvial was added a 60% oil dispersion of sodium hydride (7.9 mg, 0.20mmol). The mixture was stirred for 30 minutes. Intermediate 9 (27 mg,0.13 mmol) was added and the mixture was heated at 110° C. for 12 hours.After cooling the mixture to room temperature, it was diluted with ethylacetate (10 mL) and washed with water three times. The organic layer wasconcentrated. The residue obtained was dissolved in methanol (4 mL) andwas purified by preparative HPLC (C₁₈ column; 40-100% methanol in watercontaining 0.1% TFA) to give Example 12 as a white solid (11 mg, 16%).¹H NMR (DMSO-d₆, 500 MHz) δ 8.44 (s, 2H), 8.11 (s, 1H), 7.91-8.00 (m,1H), 7.80 (d, J=12.65 Hz, 1H), 7.55-7.65 (m, 1H), 6.30 (s, 1H),4.84-5.00 (m, 1H), 3.98-4.10 (m, 1H), 3.97-4.14 (m, 2H), 3.60-3.73 (m,2H), 3.47 (d, J=7.70 Hz, 2H), 1.93-2.07 (m, 2H), 1.61-1.78 (m, 2H), 1.19(t, J=7.42 Hz, 3H); MS (ESI) 527.3 (M+H).

Example 13 Crystal Forms of5-chloro-4-(1-(5-chloropyrimidin-2-yl)piperidin-4-yloxy)-1-(2-fluoro-4-(methylsulfonyl)phenyl)pyridin-2(1H)-one

Various crystal forms of5-chloro-4-(1-(5-chloropyrimidin-2-yl)piperidin-4-yloxy)-1-(2-fluoro-4-(methylsulfonyl)phenyl)pyridin-2(1H)-one,free base were prepared and characterized as described below.

Procedures for Characterizing the Forms

Single Crystal Data

Data were collected on a Bruker-Nonius (BRUKER AXS, Inc., 5465 EastCheryl Parkway Madison, Wis. 53711 USA) CAD4 serial diffractometer. Unitcell parameters were obtained through least-squares analysis of theexperimental diffractometer settings of 25 high-angle reflections.Intensities were measured using Cu Kα radiation (λ=1.5418 Å) at aconstant temperature with the θ-2θ variable scan technique and werecorrected only for Lorentz-polarization factors. Background counts werecollected at the extremes of the scan for half of the time of the scan.Alternately, single crystal data were collected on a Bruker-Nonius KappaCCD 2000 system using Cu Kα radiation (λ=1.5418 Å). Indexing andprocessing of the measured intensity data were carried out with theHKL2000 software package (Otwinowski, Z. et al. in MacromolecularCrystallography, Vol. 276, pp. 307-326, Carter, W. C., Jr. et al., eds.,Academic, N.Y. (1997)) in the Collect program suite. (Collect Datacollection and processing user interface: Collect: Data collectionsoftware, R. Hooft, Nonius B. V., 1998.) Alternately, single crystaldata were collected on a Bruker-AXS APEX2 CCD system using Cu Kαradiation (λ=1.5418 Å). Indexing and processing of the measuredintensity data were carried out with the APEX2 software package/programsuite (APEX2 Data collection and processing user interface: APEX2 UserManual, v1.27; BRUKER AXS, Inc., 5465 East Cheryl Parkway Madison, Wis.53711 USA).

When indicated, crystals were cooled in the cold stream of an Oxfordcryo system (Oxford Cryosystems Cryostream cooler: Cosier, J. et al., J.Appl. Cryst., 19:105 (1986)) during data collection.

The structures were solved by direct methods and refined on the basis ofobserved reflections using either the SDP (SDP, Structure DeterminationPackage, Enraf-Nonius, Bohemia N.Y. 11716. Scattering factors, includingf′ and f″, in the SDP software were taken from the “International Tablesfor Crystallography”, Vol. IV, Tables 2.2A and 2.3.1, Kynoch Press,Birmingham, England (1974)) software package with minor localmodifications or the crystallographic packages MAXUS (maXus solution andrefinement software suite: Mackay, S. et al., maXus: a computer programfor the solution and refinement of crystal structures from diffractiondata or SHELXTL⁴. The derived atomic parameters (coordinates andtemperature factors) were refined through full matrix least-squares. Thefunction minimized in the refinements was Σ_(W)(|F_(O)|−|F_(C)|)². R isdefined as Σ∥F_(O)|−|F_(C)∥/Σ|/F_(O)| whileR_(W)=[Σ_(W)(|F_(O)|−|F_(C)|)²/Σ_(W)|F_(O)|²]^(1/2) where w is anappropriate weighting function based on errors in the observedintensities. Difference maps were examined at all stages of refinement.Hydrogens were introduced in idealized positions with isotropictemperature factors, but no hydrogen parameters were varied.

X-Ray Powder Diffraction Data (PXRD)

PXRD data were obtained using a Bruker C2 GADDS. The radiation was Cu Kα(40 KV, 40 mA). The sample-detector distance was 15 cm. Powder sampleswere placed in sealed glass capillaries of 1 mm or less in diameter; thecapillary was rotated during data collection. Data were collected for3≦2θ≦35° with a sample exposure time of at least 1000 seconds. Theresulting two-dimensional diffraction arcs were integrated to create atraditional 1-dimensional PXRD pattern with a step size of 0.02 degrees2θ in the range of 3 to 35 degrees 2θ.

Differential Scanning calorimetry (DSC)

DSC experiments were performed in a TA INSTRUMENTS® model Q1000 or 2920.The sample (about 2-6 mg) was weighed in an aluminum pan and recordedaccurately recorded to a hundredth of a milligram, and transferred tothe DSC. The instrument was purged with nitrogen gas at 50 mL/min. Datawere collected between room temperature and 300° C. at 10° C./minheating rate. The plot was made with the endothermic peaks pointingdown.

Thermal Gravimetric Analysis (TGA)

TGA experiments were performed in a TA INSTRUMENTS® model Q500 or 2950.The sample (about 10-30 mg) was placed in a platinum pan previouslytared. The weight of the sample was measured accurately and recorded toa thousandth of a milligram by the instrument. The furnace was purgedwith nitrogen gas at 100 mL/min. Data were collected between roomtemperature and 300° C. at 10° C./min heating rate.

Preparation and Analysis of the Forms

The unit cell data and other properties for these examples are presentedin Table 1. The unit cell parameters were obtained from single crystalX-ray crystallographic analysis. A detailed account of unit cells can befound in Chapter 3 of Stout et al., X-Ray Structure Determination: aPractical Guide, MacMillan Co., New York (1968).

Fractional atomic coordinates for Examples 13a and b, and the conditionsat which they were measured are presented in Tables 2 and 3.

Additionally, characteristic powder X-ray diffraction peak positions(degrees 2θ±0.1)@ RT for Examples 13a, b, c, d, and e are presented inTable 4, all of which are based on high quality patterns collected witha diffractometer (CuKα) with a spinning capillary with 2θ calibratedwith a NIST other suitable standard.

Finally, FIGS. 1, 2, 3, 4, 5 and 6 present PXRD patterns for Examples13a, b, c, e, d and f. FIGS. 8 and 10 disclose the TGA of Examples 13band 13f, respectively. FIGS. 7 and 9 disclose the DSC of Examples 13band 13f, respectively.

Form Preparation, PXRD, DSC and TGA Characterization

Example 13a, Form A.5-1:5-chloro-4-(1-(5-chloropyrimidin-2-yl)piperidin-4-yloxy)-1-(2-fluoro-4-(methylsulfonyl)phenyl)pyridin-2(1H)-one,free base, was suspended at concentration in excess of 150 mg/mL inacetone. The suspension was allowed to equilibrate at room temperatureto provide a somewhat thin suspension. Part of the suspension wasfiltered and both the filtrate and the suspension were refrigerated at5° C. to provide crystals of the hemi-acetone solvate. Form A.5-1 freebase was characterized by a PXRD pattern which matches the simulatedpattern generated from the single crystal structure data.

Example 13b, Form N-2: 1 g of5-chloro-4-(1-(5-chloropyrimidin-2-yl)piperidin-4-yloxy)-1-(2-fluoro-4-(methylsulfonyl)phenyl)pyridin-2(1H)-one,free base was dissolved in 10 mL of water-free EtOAc at 77° C. Thesolution was cooled to 70° C. 10 mg of seeds of N-2 were added. To theslurry, 18 mL of n-heptane was added over 1 hour with a syringe pump.The slurry was cooled from 70° C. to 20° C. over 1 hour, and agitated at20° C. overnight. The solid was isolated by filtration, washed with 3 mLof n-heptane, dried at 50° C. in a vacuum oven overnight. Form N-2 is5-chloro-4-(1-(5-chloropyrimidin-2-yl)piperidin-4-yloxy)-1-(2-fluoro-4-(methylsulfonyl)phenyl)pyridin-2(1H)-one,free base, a neat form (without additional molecules of water orsolvent). Form N-2 was characterized by a DSC thermogram having anendothermic onset typically ca. 232° C., at higher temperatures otherevents may ensue. Form N-2 was characterized by a PXRD pattern whichmatches the simulated pattern generated from the single crystalstructure data. Form N-2 was also characterized by a TGA curve havingnegligible weight loss at up to ca. 200° C. and in agreement with thesingle-crystal structure.

Example 13c, Form AN.5-1: A suspension of5-chloro-4-(1-(5-chloropyrimidin-2-yl)piperidin-4-yloxy)-1-(2-fluoro-4-(methylsulfonyl)phenyl)pyridin-2(1H)-one,free base, at ˜200 mg/mL was prepared in acetonitrile and allowed toequilibrate at room temperature to provide a somewhat thin suspension.Part of the suspension was filtered and both the filtrate and thesuspension were refrigerated at 5° C. to provide crystals of thehemi-acetonitrile solvate.

Example 13d, E.5-1:5-chloro-4-(1-(5-chloropyrimidin-2-yl)piperidin-4-yloxy)-1-(2-fluoro-4-(methylsulfonyl)phenyl)pyridin-2(1H)-one,free base was crystallized from a solution of ethanol and heptane.

Example 13e, Form IPA.5-1: 40 mg of5-chloro-4-(1-(5-chloropyrimidin-2-yl)piperidin-4-yloxy)-1-(2-fluoro-4-(methylsulfonyl)phenyl)pyridin-2(1H)-one,free base was slurried in <1 mL of isopropyl alcohol. The slurry wasgently heated to dissolve the remaining solid. The solution was cooledto RT and allowed to slowly evaporate until crystals were observed.

Example 13f, P-6: 200 mg of5-chloro-4-(1-(5-chloropyrimidin-2-yl)piperidin-4-yloxy)-1-(2-fluoro-4-(methylsulfonyl)phenyl)pyridin-2(1H)-one,free base was taken up in 10 mL of tetrahydrofuran. The solution washeated to 50° C. to fully dissolve all of the5-chloro-4-(1-(5-chloropyrimidin-2-yl)piperidin-4-yloxy)-1-(2-fluoro-4-(methylsulfonyl)phenyl)pyridin-2(1H)-one,free base. 100 mL of n-heptane was cooled to 30° C. and then the4-(1-(5-chloropyrimidin-2-yl)piperidin-4-yloxy)-1-(2-fluoro-4-(methylsulfonyl)phenyl)pyridin-2(1H)-one,free base/THF solution was added in less than 10 seconds. The resultingprecipitate was collected by filtration, washed with about 5 mL ofn-heptane and then dried under reduced pressure to yield the materialP-6. The material P-6 was characterized by a DSC thermogram having anendothermic onset between ca. 80° C. to 120° C., at higher temperaturesother events may ensue. The material P-6 was characterized by a TGAcurve having a weight loss of ca. 12.3% up to ca. 150° C.

Example 13g, SC-3: 5.01 g of5-chloro-4-(1-(5-chloropyrimidin-2-yl)piperidin-4-yloxy)-1-(2-fluoro-4-(methylsulfonyl)phenyl)pyridin-2(1H)-one,free base was taken up in a mixture of 2.68 g of salicylic acid in 80 mLethanol. ˜100 mg of salicylic acid salt seeds of5-chloro-4-(1-(5-chloropyrimidin-2-yl)piperidin-4-yloxy)-1-(2-fluoro-4-(methylsulfonyl)phenyl)pyridin-2(1H)-one,free base were added and the resulting slurry was heated to 50° C. whereit stirred for about 16 hours. After this time, the solid was isolatedby filtration, washed with 75 mL of ethanol and then dried in a vacuumoven for about 48 hours to yield Form SC-3.

Example 13h, BZ-3: ˜50 mg of5-chloro-4-(1-(5-chloropyrimidin-2-yl)piperidin-4-yloxy)-1-(2-fluoro-4-(methylsulfonyl)phenyl)pyridin-2(1H)-one,free base was slurried in 2 mL of 0.25 M benzoic acid in ethanol. Seedsof co-crystals of form SC-3 were added. The mixture was heated to 50° C.where the slurry was stirred for about 48 hours. After this time, theresulting shiny was analyzed by PXRD and proton NMR, which indicated thepresence of co-crystals of forms SC-3 and BZ-3. Form BZ-3 was collectedby filtration from the slurry to yield Form BZ-3.

TABLE 1 Unit Cell Parameters Example Form T a (Å) b (Å) c (Å) α° β° 13aA.5-1 25 9.575(2) 11.414(2) 11.428(2) 87.624(9) 83.785(9) 13b N-2 2510.951(2) 11.455(2) 17.920(2) 90 95.865(8) 13c AN.5-1 25 9.620(2)11.469(3) 11.289(3) 85.84(1) 84.14(1) 13d E.5-1 25 9.612(1) 11.330(2)11.332(2) 88.711(6) 84.482(9) 13e IPA.5-1 25 9.538(1) 11.345(2)11.595(2) 89.523(6) 83.94(1) 13g SC-3 25 10.0602(4) 10.3671(4)14.9367(9) 103.612(3) 100.089(3) 13h BZ-3 25 10.085(2) 10.393(2)14.757(4) 103.568(9) 99.422(8) Example γ° Z Vm Sg R Dcalc 13a 79.49(1) 2610 Pbar1 0.047 1.476 13b 90 4 559 P2₁/c 0.044 1.525 13c 79.71(1) 2 609Pbar1 0.050 1.457 13d 79.118(9) 2 603 Pbar1 0.042 1.477 13e 79.59(1) 2614 Pbar1 0.045 1.471 13g 104.309(2) 2 711 Pbar1 0.029 1.522 13h105.25(1) 2 704 Pbar1 0.039 1.499The variables used in Table 1 are defined below:

T=temperature in Centigrade for the crystallographic data;

Z=number of drug molecules per asymmetric unit;

Vm=V (unit cell)/(Z drug molecules per cell);

sg=space group;

R=residual index (I>3 sigma(I)); and

dcalc=calculated crystal density.

TABLE 2 Fractional Atomic Coordinates for Example 13a, Form A.5-1, at T= 25° C. Atom x y Z S1 1.13374 −0.2169 0.80291 Cl2 0.54743 0.53270.83243 Cl3 0.24737 1.17145 0.01993 N4 0.83684 0.27374 0.68828 O5 0.65260.61583 0.60375 F6 0.80225 0.07827 0.56904 O7 0.98475 0.25822 0.51796 N90.595 0.8385 0.30754 N10 0.5153 1.0328 0.2515 C11 0.7195 0.5046 0.6241N12 0.4407 0.87201 0.16221 C8 0.9017 0.15453 0.72147 C13 0.8856 0.058980.65699 C14 0.7357 0.34098 0.76488 C15 0.6768 0.4527 0.73543 C16 0.82120.43747 0.54976 C17 0.889 0.31944 0.5796 C18 0.9828 0.13564 0.81385 C190.9527 −0.0552 0.68092 C20 0.5156 0.91685 0.23859 C21 0.6506 0.806330.51148 O22 1.1937 −0.214 0.91181 O23 1.0458 −0.302 0.7898 C24 1.0371−0.07232 0.77362 C25 0.431 1.10856 0.1848 C26 0.6018 0.64039 0.3979 C271.0509 0.0211 0.84145 C28 0.6291 0.7112 0.2859 C29 0.6872 0.675040.49064 Atom x y z C30 0.3621 0.9496 0.09716 C31 0.3527 1.0704 0.10576C32 0.6729 0.8773 0.3969 C33 1.272 −0.2343 0.6888 C34 1.0186 0.46140.9539 O35 1.0397 0.3945 0.8718 C36 0.8663 0.5127 0.9935 H33A 1.23356−0.2369 0.61499 H33B 1.33708 −0.3071 0.70145 H33C 1.32159 −0.16830.68754 H27 1.10568 0.00687 0.90781 H19 0.94098 −0.1195 0.63348 H180.99441 0.20103 0.8599 H14 0.70497 0.30857 0.84012 H16 0.84967 0.468760.47342 H29 0.7871 0.65411 0.4647 H26A 0.50188 0.65627 0.4249 H26B0.6314 0.55695 0.3828 H21A 0.55211 0.82646 0.54212 H21B 0.70969 0.827440.5671 H28A 0.57027 0.692 0.22915 H28B 0.72779 0.68967 0.25629 H32A0.77305 0.86479 0.3707 H32B 0.63878 0.96056 0.41064 H30 0.30902 0.921820.04073 H25 0.42609 1.19284 0.19124 H36A 0.8232 0.55762 0.92973 H36B0.81533 0.44929 1.01757 H36C 0.86319 0.56425 1.05842

TABLE 3 Fractional Atomic Coordinates for Example 13b, Form N-2, at T =25° C. Atom x y Z Cl1 0.86027 −0.0535 0.03838 S2 0.80743 0.65016 0.28459Cl3 −0.1221 −0.5168 −0.1537 F4 0.55509 0.32858 0.1507 O6 0.63209 −0.15180.07863 O7 0.57348 0.13963 0.26131 C9 0.662 −0.0568 0.12021 N10 0.29855−0.3261 0.02283 N11 0.09381 −0.3115 −0.0205 C12 0.6592 0.3585 0.19311 N50.72625 0.15622 0.18479 C8 0.7484 0.2744 0.21022 C13 0.7685 0.00440.10187 C14 0.6731 0.4723 0.2167 C15 0.8733 0.4202 0.27682 C16 0.796850.1088 0.13306 C17 0.8567 0.3063 0.25223 C18 0.7822 0.5013 0.25912 C190.5187 −0.2126 0.08858 O20 0.92398 0.65714 0.32632 C21 0.1972 −0.3751−0.0143 C22 0.6285 0.0951 0.21155 C23 0.407 −0.1441 0.05672 N24 0.2093−0.4822 −0.0437 C25 0.5993 −0.0136 0.17587 C26 0.2911 −0.216 0.06277Atom x y z C27 0.4067 −0.3959 0.04841 C28 0.5246 −0.3261 0.04582 C290.0028 −0.3574 −0.0623 O30 0.7846 0.71873 0.21817 C31 0.1108 −0.5244−0.0853 C32 0.0038 −0.4627 −0.0971 C33 0.6959 0.684 0.34384 H33A 0.705160.76375 0.35989 H33B 0.7057 0.63351 0.38679 H33C 0.61568 0.67307 0.31778H14 0.60814 0.52726 0.20393 H15 0.94768 0.44195 0.30658 H17 0.920150.24928 0.26365 H16 0.86712 0.15028 0.119 H25 0.53269 −0.0574 0.19289H28A 0.53407 −0.3085 −0.0057 H28B 0.59354 −0.3713 0.06684 H19 0.51264−0.2262 0.14093 H23A 0.40236 −0.0718 0.08336 H23B 0.41431 −0.12830.00475 H26A 0.22043 −0.1731 0.04195 H26B 0.28421 −0.2317 0.11479 H27A0.40174 −0.4183 0.09963 H27B 0.40991 −0.4645 0.01797 H31 0.11339 −0.6003−0.1077 H29 −0.0794 −0.3159 −0.068

TABLE 4 Characteristic powder X-ray diffraction peak positions (degrees2θ ± 0.1)@ RT for Examples 13a, b, d, c, d, and e based on a highquality pattern collected with a diffractometer (CuKα) with a spinningcapillary with 2θ calibrated with a NIST other suitable standard. Exp13a Exp 13b Exp 13c Exp 13d Exp 13e 16.9 9.9 10.8 15.7 15.4 21.8 11.218.3 16.9 16.0 23.0 12.2 22.4 18.3 17.0 13.5 25.8 18.5 19.3 14.4 23.117.5

Assay(s) for GPR119 G Protein-Coupled Receptor Activity

The in vitro modulation of recombinant human GPR119 was determined asfollows.

Tet-Inducible cAMP Assay

A human-mouse chimeric GPR119 expression construct encoding 3 copies ofthe FLAG epitope tag, the first 198 amino acids of human GPR119 and theC-terminal 137 amino acids of the mouse receptor was cloned into atetracycline inducible vector pcDNA5/FRT/TO (Invitrogen #V6520-20),which includes a hygromycin-resistance marker. Tightly controlledreceptor expression was achieved by stable integration of this constructinto the genome of a specific host cell line, Flp-In-T-Rex-HEK293,expressing the tetracycline repressor (Invitrogen). Once a stablehygromycin-resistant cell line was generated, the cells were maintainedat 37° C. in a humidified 5% CO₂ atmosphere in culture medium consistingof Dulbecco's modified Eagle's medium (DMEM; Invitrogen #11960)supplemented with 2 mM L-glutamine, 10% fetal bovine serum, 200 μg/mlhygromycin B, and 15 μg/ml blasticidin.

Forty-eight hours prior to the cAMP accumulation assay, cells stablyexpressing the chimeric human/mouse GPR119 construct were seeded at adensity of 4×10³ cells/well in 384 well poly-D-lysine coated solid whiteplates (BD #35-6661) and grown at 37° C. in a humidified 5% CO₂atmosphere in culture medium supplemented with 1 μg/ml tetracycline toinduce expression of the receptor. On the day of the assay, medium wasremoved and cells were incubated for 50 min. at 37° C. in a humidified5% CO₂ atmosphere in 20 μl/well of assay buffer (phosphate-bufferedsaline with Ca²⁺ and Mg²⁺, 12 mM glucose, 0.1 mMisobutyl-methyl-xanthine, 0.1% fatty-acid free bovine serum albumin)with the desired concentration of compound added from a concentratedstock dissolved in dimethyl sulfoxide (DMSO) to give a finalconcentration of 1% DMSO in the assay. cAMP accumulation was measuredusing the CisBio homogeneous time resolved fluorescence (HTRF) assay kit(#62AM2PEC) following the manufacturer's protocol. Briefly, 10 μl eachof the cAMP-HTRF fluorescence detection reagents were added to eachwell, and the samples were incubated for 40 min. at room temperature.Fluorescence was excited at 320 nm and measured at 665 and 620 nm usingthe Envision instrument (Perkin Elmer), the fluorescence ratio of665/620 was calculated and converted to nanomolar concentrations of cAMPin each well by interpolation from a cAMP standard curve. Theconcentration-response curves and EC₅₀ values were calculated with afour parameter logistic curve fit equation utilizing Excel/XLfitsoftware (Microsoft and IDBS). The EC₅₀ value was calculated as theconcentration of agonist which increased the cAMP concentration to avalue halfway between the baseline and the maximum.

Compounds of the present invention were tested in the Tet-inducible cAMPassay described immediately above and the results shown in Table 5 belowwere obtained.

TABLE 5 Example GPR119 EC₅₀ (nM) 1 8 2 12 3 7 4 5 5 3 6 4 8 8 9 13 10 211 6Mouse Oral Glucose Tolerance Test

Twenty four (24) male C57BL/6J mice (8-10 weeks old, average weight 28g) were randomized into 4 groups (1 mouse/cage) of 6 mice per groupbased on fed plasma glucose and body weight. Prior to initiating thestudy, mice were fasted overnight and the next morning they were weighedand placed in the experimental lab. After 30 min in the environment, themice were bled via tail tip at −60 min and immediately given their firstoral administration of vehicle (40% PEG400, 10% Cremophor EL, 50% water)or compound solutions (5 ml/kg). At time 0 the mice were bled and given50% glucose (2 g/kg) to initiate the oral glucose tolerance test (oGTT).The mice were bled 30, 60 and 120 min after the glucose load. Bloodsamples were drawn into potassium EDTA, placed on ice during the studyand subsequently centrifuged for 10 min at 3000 rpm at 4° C. Plasmasamples were diluted 11-fold for glucose analysis in the COBAS MIRA®System (Roche Diagnostics). Area under the curve was calculated from theplasma glucose time course data using the trapezoid rule with fastingplasma glucose as the baseline (GraphPad Prism Software). Thestatistical significance of the changes in the glucose AUCs resultingfrom the different treatments was determined by one-way ANOVA followedby Dunnett's test using the vehicle group as the control (JMP software,release 5.1.2).

Find below in Table 6 data for compared compounds (See WO 2009/012275A1). The comparative data shows the unexpected significant reduction inplasma glucose at significantly lower doses of the compounds of thepresent invention.

TABLE 6 Comparative In vivo Data Minimally efficacious Dose GlucoseLowering Compound (mg/kg) (%) Example 3 30 −29% WO 2009/012275 A1Example 142 1 −33% WO 2009/012275 A1 Example 190 10 −18% WO 2009/012275A1 Example 224 0.3 −30% WO 2009/012275 A1 Example 229 1 −20% WO2009/012275 A1 Example 265 3 −25% WO 2009/012275 A1 Example 268 3 −23%WO 2009/012275 A1 Example 1 0.1 −24% Present Invention Example 2 0.1−29% Present Invention Example 3 0.1 −28% Present Invention Example 40.03 −24% Present Invention Example 5 0.06 −29% Present InventionExample 6 0.1 −36% Present Invention Example 8 0.03 −26% PresentInventionMetabolic Stability in Liver Microsomes Test

Human liver microsomes were purchased from BD-Biosciences (Woburn,Mass.). The test compound was received as a 3.5 mM stock solution in 100percent dimethyl sulfoxide (“DMSO”, Sigma Aldritch). The compoundsolution was diluted to create a 50 μM acetonitrile (“ACN”, SigmaAldritch) solution containing 1.4% DMSO, which is then used as a100-fold stock for incubation with microsomes. The test compound,β-nicotinamide adenine dinucleotide phosphate (“NADPH”, AppliChem Inc.)and liver microsome solutions are combined for incubation in threesteps:

1) 450 μl of liver microsome suspension, protein concentration of 1.1mg/ml in 100 mM sodium (+)/phosphate (“NaP_(i)”, pH 7.4, Sigma Aldritch)buffer, 5 mM magnesium chloride (“MgCl₂, Sigma Aldritch) buffer, ispre-warmed at 37° C.;

2) 5 μl of 50 μM test compound (98.6% ACN, 1.4% DMSO) is added to thesame tube and pre-incubated at 37° C. for 5 minutes; and

3) The reaction is initiated by the addition of 50 μl of pre-warmed 10mM NADPH solution in 100 mM NaP_(i), pH 7.4.

Reaction components are mixed well and then 65 μl are immediatelytransferred into 130 μl of quench/stop solution (zero-time point, T₀).The reactions are incubated at 37° C. for 5, 10, 15, 30 and 45 minutesand at each time-point a 65 μl aliquot is transferred into 130 μl ofquench solution. ACN containing Internal Standard (100 ng/ml), is usedas the quench solution to terminate metabolic reactions. The quenchedmixtures are centrifuged at 1500 rpm (˜500×g) in an Allegra X-12centrifuge, SX4750 rotor (Beckman Coulter Inc., Fullerton, Calif.) forfifteen minutes to pellet denatured microsomes. A volume of 90 μl ofsupernatant extract, containing the mixture of parent compound and itsmetabolites, is then transferred to a separate 96-well plate forLC/MS-MS analysis to determine the percent of parent compound that isremaining in the mixture. Peak integration is performed on all samplesusing the Hepatic Clearance Calculator of QuickCalc by Gubbs, Inc. Thepercent remaining calculation is performed by comparing the LC-MS/MSpeak areas from the samples at each time point to those from the T₀samples for each compound. T_(1/2) values are calculated from linearregression of the LN (% Remaining) over time, and the slope of thatregression (Kel) is used to calculate T_(1/2), using the followingequation: T_(1/2)=−0.693/Kel.

Find below in Table 7 data for compared compounds (See WO 2009/012275A1). Generally, the comparative data shows the unexpected improvement inmetabolic stability of the compounds of the present invention.

TABLE 7 Additional comparative In vitro Data Human Liver MicrosomeCompound Half-life (minutes) Example 142 33 WO 2009/012275 A1 Example151 71 WO 2009/012275 A1 Example 190 122 WO 2009/012275 A1 Example 224 4WO 2009/012275 A1 Example 229 30 WO 2009/012275 A1 Example 265 47 WO2009/012275 A1 Example 268 59 WO 2009/012275 A1 Example 1 180 PresentInvention Example 2 147 Present Invention Example 3 108 PresentInvention Example 4 57 Present Invention Example 5 105 Present InventionExample 6 39 Present Invention Example 8 120 Present Invention Example 988 Present Invention Example 10 35 Present Invention Example 11 51Present Invention

Surprisingly, it was discovered that the compounds of the presentinvention possess beneficial pharmacological characteristics, such as,the combination of potent GPR119 efficacy, improved glucose reduction atlower dosage levels and metabolic stability in comparison to compoundsknow in the art. See Tables 5, 6 and 7. For example, see Example 1 ofthe present invention and Example 224 of WO 2009/012275 A1. Example 1 ofthe present invention has a GPR119 EC₅₀ of 8 nM, a 24% reduction inglucose at 0.1 mg/kg, and a half-life of 180 minutes. In comparison,Example 224 of WO 2009/012275 A1 while having similar activity againstGPR119 (an GPR119 EC₅₀ of 4 nM) is three times less effective inreducing glucose (0.3 mg/kg to get a 30% reduction in glucose) and 45times less stable (4 minute half-life).

Utilities and Combinations

A. Utilities

The compounds of the present invention possess activity as agonists ofthe GPR119 receptor, and, therefore, may be used in the treatment ofdiseases associated with GPR119 receptor activity. Via the activation ofGPR119 receptor, the compounds of the present invention may preferablybe employed to increase insulin production or increase GLP-1 secretionor both.

Accordingly, the compounds of the present invention can be administeredto mammals, preferably humans, for the treatment of a variety ofconditions and disorders, including, but not limited to, treating,preventing, or slowing the progression of diabetes and relatedconditions, microvascular complications associated with diabetes,macrovascular complications associated with diabetes, cardiovasculardiseases, Metabolic Syndrome and its component conditions, inflammatorydiseases and other maladies. Consequently, it is believed that thecompounds of the present invention may be used in preventing,inhibiting, or treating diabetes, hyperglycemia, impaired glucosetolerance, insulin resistance, hyperinsulinemia, retinopathy,neuropathy, nephropathy, wound healing, atherosclerosis and its sequelae(acute coronary syndrome, myocardial infarction, angina pectoris,peripheral vascular disease, intermittent claudication, myocardialischemia, stroke, heart failure), Metabolic Syndrome, hypertension,obesity, dyslipidemia, hyperlipidemia, hypertriglyceridemia,hypercholesterolemia, low HU, high LDL, vascular restenosis, peripheralarterial disease, lipid disorders, bone disease (includingosteoporosis), PCOS, HIV protease associated lipodystrophy, andglaucoma, and treatment of side-effects related to diabetes,lipodystrophy and osteoporosis from corticosteroid treatment.

Metabolic Syndrome or “Syndrome X” is described in Ford et al., J. Am.Med. Assoc., 287:356-359 (2002) and Arbeeny et al., Curr. Med.Chem.—Endoc. & Metab. Agents, 1:1-24 (2001).

B. Combinations

The present invention includes within its scope pharmaceuticalcompositions comprising, as an active ingredient, a therapeuticallyeffective amount of at least one of the compounds of Formula I, alone orin combination with a pharmaceutical carrier or diluent. Optionally,compounds of the present invention can be used alone, in combinationwith other compounds of the invention, or in combination with one ormore other therapeutic agent(s), e.g., an antidiabetic agent or otherpharmaceutically active material.

The compounds of the present invention may be employed in combinationwith one or more other suitable therapeutic agents useful in thetreatment of the aforementioned disorders including: anti-diabeticagents, anti-hyperglycemic agents, anti-hyperinsulinemic agents,anti-retinopathic agents, anti-neuropathic agents, anti-nephropathicagents, anti-atherosclerotic agents, anti-ischemic agents,anti-hypertensive agents, anti-obesity agents, anti-dyslipidemic agents,anti-dyslipidemic agents, anti-hyperlipidemic agents,anti-hypertriglyceridemic agents, anti-hypercholesterolemic agents,anti-restenotic agents, anti-pancreatic agents, lipid lowering agents,appetite suppressants, treatments for heart failure, treatments forperipheral arterial disease and anti-inflammatory agents.

Examples of suitable anti-diabetic agents for use in combination withthe compounds of the present invention include insulin and insulinanalogs (e.g., LysPro insulin, inhaled formulations comprising insulin);glucagon-like peptides; sulfonylureas and analogs (e.g., chlorpropamide,glibenclamide, tolbutamide, tolazamide, acetohexamide, glypizide,glyburide, glimepiride, repaglinide, meglitinide); biguanides (e.g.,metformin, phenformin, buformin); alpha2-antagonists and imidazolines(e.g., midaglizole, isaglidole, deriglidole, idazoxan, efaroxan,fluparoxan); other insulin secretagogues (e.g., linogliride,insulinotropin, exendin-4,N,N-dimethyl-N′-[2-(4-morpholinyl)phenyl]guanidine (E)-2-butenedioatesalt (BTS-675820),(−)-N-(trans-4-isopropylcyclohexanecarbonyl)-D-phenylalanine (A-4166));thiazolidinediones and PPAR-gamma agonists (e.g., ciglitazone,pioglitazone, troglitazone, rosiglitazone); PPAR-alpha agonists e.g.,fenofibrate, gemfibrozil); PPAR alpha/gamma dual agonists (e.g.,muraglitazar, peliglitazar, aleglitazar); SGLT2 inhibitors (e.g.,3-(benzo[b]furan-5-yl)-2′,6′-dihydroxy-4′-methylpropiophenone-2′-O-(6-O-methoxycarbonyl)-β-d-glucopyranoside(T-1095 Tanabe Seiyaku), phlorizin, TS-033 (Taisho), dapagliflozin(BMS), sergiflozin (Kissei), AVE 2268 (Sanofi-Aventis)), canagliflozin;11-beta-hydroxysteriod dehydrogenase type I inhibitors (e.g., AMG221,INCB13739); dipeptidyl peptidase-IV (DPP4) inhibitors (e.g.,saxagliptin, sitagliptin, vildagliptin, alogliptin and denagliptin);glucagon-like peptide-1 (GLP-1) receptor agonists (e.g., Exenatide(Byetta), NN2211 (Liraglutide, Novo Nordisk), AVE0010 (Sanofi-Aventis),R1583 (Roche/Ipsen), SUN E7001 (Daiichi/Santory), GSK-716155 (GSK/HumanGenome Sciences) and Exendin-4 (PC-DACTM); aldose reductase inhibitors(e.g., those disclosed in WO 99/26659); RXR agonists (e.g., reglitazar(JTT-501),5-[[6-[(2-fluorophenyl)methoxy]-2-naphthalenyl]methyl]-2,4-thiazolidinedione(MCC-555),5-[[3-(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalenyl)-4-(trifluoromethoxy)-phenyl]methylene]-2,4-thiazolidinedione(MX-6054), DRF2593, farglitazar,(±)-5-[(2,4-dioxothiazolidin-5-yl)methyl]-2-methoxy-N-[[(4-trifluoromethyl)phenyl]-methyl]benzamide(KRP-297),6-[1-(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalenyl)cyclopropyl]-3-pyridinecarboxylicacid (LG100268)); fatty acid oxidation inhibitors (e.g., clomoxir,etomoxir; α-glucosidase inhibitors: precose, acarbose, miglitol,emiglitate, voglibose,2,6-dideoxy-2,6-imino-7-O-β-D-glucopyranosyl-D-glycero-L-gulo-heptitol(MDL-25,637), camiglibose); beta-agonists (e.g., methylester[4-[(2R)-2-[[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]propyl]phenoxy]-aceticacid (BRL 35135),2-[4-[(2S)-2-[[(2S)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]propyl]phenoxy]-aceticacid (BRL 37344),4-[(3R)-3-[bis[(2R)-2-hydroxy-2-phenylethyl]amino]butyl]-benzamide (Ro16-8714),2-[4-[2-[[(2S)-2-hydroxy-3-phenoxypropyl]amino]ethoxy]phenoxy]-N-(2-methoxyethyl)-acetamide(ICI D7114),5-[(2R)-2-[[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]propyl]-3-benzodioxole-2,2-dicarboxylicacid, disodium salt (CL 316,243), TAK-667, AZ40140); phosphodiesteraseinhibitors, both cAMP and cGMP type (e.g., sildenafil,9-((1S,2R)-2-fluoro-1-methylpropyl)-2-methoxy-6-(1-piperazinyl)purinehydrochloride (L-686398), L-386,398); amylin agonists (e.g.,pramlintide); lipoxygenase inhibitors (e.g., masoprocal); somatostatinanalogs (e.g., lanreotide, seglitide, octreotide); glucagon antagonists(e.g., BAY 276-9955); insulin signaling agonists, insulin mimetics,PTP1B inhibitors (e.g.,2-[2-(1,1-dimethyl-2-propenyl)-1H-indol-3-yl]-3,6-dihydroxy-5-[7-(3-methyl-2-butenyl)-1H-indol-3-yl]-2,5-cyclohexadiene-1,4-dione(L-783281), TER17411, TER17529); gluconeogenesis inhibitors (e.g.,GP3034); somatostatin analogs and antagonists; antilipolytic agents(e.g., nicotinic acid, acipimox, N-cyclohexyl-2′-O-methyl-adenosine (WAG994)); glucose transport stimulating agents (e.g.,4-chloro-α-[(4-methylphenyl)sulfonyl]-benzeneheptanoic acid(BM-130795)); glucose synthase kinase inhibitors (e.g., lithiumchloride, CT98014, CT98023); galanin receptor agonists; Chemokinereceptor antagonist CCR2/5 (e.g., NCB3284, MK-0812, INCB8696, maraviroc(Pfizer) and vicriviroc); thyroid receptor agonists (e.g., KB-2115(KaroBio)); glucokinase activators (e.g., RO-27-4375, RO-28-1675(Roche),6-[[3-[(1S)-2-methoxy-1-methylethoxy]-5-[(1S)-1-methyl-2-phenylethoxy]benzoyl]amino]-3-pyridinecarboxylicacid (GKA-50 AstraZeneca)); GPR40 modulators (e.g.,(S)-4-(dimethylamino)-3-(4-((4-methyl-2-p-tolylthiazol-5-yl)methoxy)phenyl)-4-oxobutanoicacid,6-chloro-2-(4-chlorobenzylthio)-1-(4-(methoxyethoxy)phenyl)-1H-benzo[d]imidazole,TAK-875, CNX011, and P1736).

Examples of suitable lipid lowering agents and anti-atheroscleroticagents for use in combination with the compounds of the presentinvention include one or more MTP/ApoB secretion inhibitors (e.g.,dirlopatide,N-(2,2,2-trifluoroethyl)-9-[4-[4-[[[4′-(trifluoromethyl)[1,1′-biphenyl]-2-yl]carbonyl-]amino]-1-piperidinyl]butyl]-9H-fluorene-9-carboxamide,methanesulfonate, CP-741952 (Pfizer), SLx-4090 (Surface Logix)); HMG CoAreductase inhibitors (e.g., atorvastatin, rosuvastatin, simvastatin,pravastatin, lovastatin, fluvastatin); squalene synthetase inhibitors,PPAR alpha agonists and fibric acid derivatives (e.g., fenofibrate,gemfibrozil); ACAT inhibitors; lipoxygenase inhibitors; cholesterolabsorption inhibitors (e.g., ezetimibe); thyroid receptor agonists(e.g., as set forth above); Ileal Na+/bile acid cotransporter inhibitors(e.g., compounds as disclosed in Drugs of the Future, 24:425-430 (1999);upregulators of LDL receptor activity (e.g.,(3R)-3-[(13R)-13-hydroxy-10-oxotetradecyl]-5,7-dimethoxy-1(3H)-isobenzofuranone(Taisho Pharmaceutical Co. Ltd.) and(3α,4α,5α)-4-(2-propenyl)-cholestan-3-ol (Eli Lilly); bile acidsequestrants (e.g., WELCHOL®, COLESTID®, LoCholest and QUESTRAN®; andfibric acid derivatives, such as Atromid, LOPID® and Tricot);cholesterol ester transfer protein inhibitors (e.g., torcetrapib and(2R)-3-{[3-(4-chloro-3-ethyl-phenoxy)-phenyl]-[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino}-1,1,1-trifluoro-2-propanol);nicotinic acid and derivatives thereof (e.g., niacin, acipimox); PCSK9inhibitors; LXR agonists (e.g., those disclosed in U.S. PatentApplication Publication Nos. 2003/01814206, 2005/0080111, and2005/0245515); lipoxygenase inhibitors (e.g., such as benzimidazolederivatives, as disclosed in WO 97/12615, 15-LO inhibitors, as disclosedin WO 97/12613, isothiazolones, as disclosed in WO 96/38144, and 15-LOinhibitors, as disclosed by Sendobry et al., “Attenuation ofdiet-induced atherosclerosis in rabbits with a highly selective15-lipoxygenase inhibitor lacking significant antioxidant properties”,Brit. J. Pharmacology, 120:1199-1206 (1997), and Cornicelli et al.,“15-Lipoxygenase and its Inhibition: A Novel Therapeutic Target forVascular Disease”, Current Pharmaceutical Design, 5:11-20 (1999)).

Preferred hypolipidemic agents are pravastatin, lovastatin, simvastatin,atorvastatin, fluvastatin, cerivastatin, atavastatin, and rosuvastatin.

Examples of suitable anti-hypertensive agents for use in combinationwith the compounds of the present invention include beta adrenergicblockers, calcium channel blockers (L-type and T-type; e.g., diltiazem,verapamil, nifedipine, amlodipine and mybefradil), diuretics (e.g.,chlorothiazide, hydrochlorothiazide, flumethiazide, hydroflumethiazide,bendroflumethiazide, methylchlorothiazide, trichloromethiazide,polythiazide, benzthiazide, ethacrynic acid tricrynafen, chlorthalidone,furosemide, musolimine, bumetanide, triamtrenene, amiloride,spironolactone), renin inhibitors (e.g., aliskiren), ACE inhibitors(e.g., captopril, zofenopril, fosinopril, enalapril, ceranopril,cilazopril, delapril, pentopril, quinapril, ramipril, lisinopril), AT-1receptor antagonists (e.g., losartan, irbesartan, valsartan), ETreceptor antagonists (e.g., sitaxsentan, atrsentan, and compoundsdisclosed in U.S. Pat. Nos. 5,612,359 and 6,043,265), Dual ET/AIIantagonist (e.g., compounds disclosed in WO 00/01389), neutralendopeptidase (NEP) inhibitors, vasopeptidase inhibitors (dual NEP-ACEinhibitors) (e.g., omapatrilat and gemopatrilat), nitrates, centralalpha agonists (e.g., clonidine), alpha1 blockers (e.g., prazosin),arterial vasodilators (e.g., minoxidil), sympatolytics (e.g.,resperine), renin inhibitors (e.g., Aliskiren (Novartis)).

Examples of suitable anti-obesity agents for use in combination with thecompounds of the present invention include a cannabinoid receptor 1antagonist or inverse agonist (e.g., rimonabant,(4S)-3-(4-chlorophenyl)-N-[(4-chlorophenyl)sulfonyl]-4,5-dihydro-N′-methyl-4-phenyl-1H-pyrazole-1-carboximidamide(SLV 319), CP-945598 (Pfizer), Surinabant (SR-147778, Sanofi-Aventis),N-[(1S,2S)-3-(4-chlorophenyl)-2-(3-cyanophenyl)-1-methylpropyl]-2-methyl-2-{[5-(trifluoromethyl)pyridin-2-yl]oxy}propanamide(Merck) and those discussed in Hertzog, D. L., Expert Opin. Ther.Patents, 14:1435-1452 (2004)); a beta 3 adrenergic agonist (e.g.,rafabegron (AJ9677, Takeda/Dainippon),N-[4-[2-[[(2S)-3-[(6-amino-3-pyridinyl)oxy]-2-hydroxypropyl]amino]ethyl]phenyl]-4-(1-methylethyl)-benzenesulfonamide(L750355, Merck), or CP331648 (Pfizer), or other known beta 3 agonists,as disclosed in U.S. Pat. Nos. 5,541,204, 5,770,615, 5,491,134,5,776,983, and 5,488,064, with rafabegron,N-[4-[2-[[(2S)-3-[(6-amino-3-pyridinyl)oxy]-2-hydroxypropyl]amino]ethyl]phenyl]-4-(1-methylethyl)-benzenesulfonamide,and CP331648 being preferred); a lipase inhibitor (e.g., orlistat orcetilistat, with orlistat being preferred); a serotonin andnorepinephrine reuptake inhibitor (e.g., sibutramine, Abbott andtesofensine, Neurosearch) with sibutramine being preferred; a dopaminereuptake inhibitor (e.g., buproprion, GSK); or 5-HT_(2C) agonist, (e.g.,lorcaserin hydrochloride (Arena), WAY-163909[(7bR,10aR)-1,2,3,4,8,9,10,10a-octahydro-7bH-cyclopenta-[b][1,4]diazepino[6,7,1hi]indole],with lorcaserin hydrochloride being preferred); 5-HT6 receptorantagonists (Suven, Biovitrum, Epix), anti-epileptics topiramate(Johnson & Johnson) and zonisamide, a ciliary neurotrophic factoragonist (e.g., AXOKINE® (Regeneron); brain-derived neurotrophic factor(BDNF), orexin antagonists, histamine receptor-3 (H3) modulators,melanin-concentrating hormone receptor (MCHR) antagonists (e.g.,GSK-856464 (GlaxoSmithKline), T-0910792 (Amgen)); diacylglycerolacyltransferase (DGAT) inhibitors (e.g., BAY-74-4113 (Bayer),PF-04620110, and LCQ908); acetyl-CoA carboxylase (ACC) inhibitors (e.g.,N-(4-(4-(4-isopropoxyphenoxy)phenyl)but-3-yn-2-yl)acetamide (A-80040,Abbott),(R)-anthracen-9-yl(3-(morpholine-4-carbonyl)-1,4′-bipiperidin-1′-yl)methanone(CP-640186, Pfizer)), SCD-1 inhibitors as described by Jiang et al.,Diabetes, 53 (2004), (abs 653-p); amylin receptor agonists (e.g.,compounds disclosed in WO 2005/025504); thyroid receptor agonists (e.g.,as set forth above); growth hormone secretagogue receptor (GHSR)antagonists (e.g., A-778193 (Abbott), leptin and leptin mimetics (e.g.,OB-3 (Aegis/Albany Medical College), leptin analogs A-100 and A-200(Amgen), CBT-001452 (Cambridge Biotechnology), ML-22952 (Millennium)),PYY receptor agonist (e.g., AC-162352 (Amylin), PYY-3-36 (Emishere),PYY(3-36)NH2 (Unigene)), NPY-Y4 agonists (7TM Pharma WO 2005/089786(A2,A3)-1), NPY-5 antagonists (e.g., NPY5RA-972 (AstraZeneca),GW-594884A (GlaxoSmithKline), J-104870 (Banyu)); MTP/apoB secretioninhibitors (as set forth above), and/or an anorectic agent.

The anorectic agent which may be optionally employed in combination withcompounds of the present invention include dexamphetamine, phentermine,phenylpropanolamine, or mazindol, with dexamphetamine being preferred.

Other compounds that can be used in combination with the compounds ofthe present invention include CCK receptor agonists (e.g., SR-27895B);galanin receptor antagonists; MCR-4 antagonists (e.g.,N-acetyl-L-norleucyl-L-glutaminyl-L-histidyl-D-phenylalanyl-L-arginyl-D-tryptophyl-glycinamide,(HP-228); urocortin mimetics, CRF antagonists, and CRF binding proteins(e.g., mifepristone (RU-486), urocortin).

Further, the compounds of the present invention may be used incombination with HIV protease inhibitors, including but not limited toREYATAZ® and KALETRA®.

Examples of suitable memory enhancing agents, anti-dementia agents, orcognition promoting agents for use in combination with the compounds ofthe present invention include, but are not limited to ARICEPT®,razadyne, donepezil, rivastigmine, galantamine, memantine, tacrine,metrifonate, muscarine, xanomelline, deprenyl and physostigmine.

Examples of suitable anti-inflammatory agents for use in combinationwith the compounds of the present invention include, but are not limitedto, NSAIDS, prednisone, acetaminophen, aspirin, codeine, fentanyl,ibuprofen, indomethacin, ketorolac, morphine, naproxen, phenacetin,piroxicam, sufentanyl, sunlindac, interferon alpha, prednisolone,methylprednisolone, dexamethazone, flucatisone, betamethasone,hydrocortisone, beclomethasone, REMICADE®, ORENCIA®, and ENBREL®.

The aforementioned patents and patent applications are incorporatedherein by reference.

The above other therapeutic agents, when employed in combination withthe compounds of the present invention may be used, for example, inthose amounts indicated in the Physicians' Desk Reference, as in thepatents set out above, or as otherwise determined by one of ordinaryskill in the art.

Dosage and Formulation

The compounds of this disclosure can be administered in such oral dosageforms as tablets, capsules (each of which includes sustained release ortimed release formulations), pills, powders, granules, elixirs,tinctures, suspensions, syrups, and emulsions. They may also beadministered in intravenous (bolus or infusion), intraperitoneal,subcutaneous, or intramuscular form, all using dosage forms well knownto those of ordinary skill in the pharmaceutical arts. They can beadministered alone, but generally will be administered with apharmaceutical carrier selected on the basis of the chosen route ofadministration and standard pharmaceutical practice.

The dosage regimen for the compounds of the present invention will, ofcourse, vary depending upon known factors, such as the pharmacodynamiccharacteristics of the particular agent and its mode and route ofadministration; the species, age, sex, health, medical condition, andweight of the recipient; the nature and extent of the symptoms; the kindof concurrent treatment; the frequency of treatment; the route ofadministration, the renal and hepatic function of the patient, and theeffect desired. A physician or veterinarian can determine and prescribethe effective amount of the drug required to prevent, counter, or arrestthe progress of the disorder.

By way of general guidance, the daily oral dosage of each activeingredient, when used for the indicated effects, will range betweenabout 0.001 to 1000 mg/kg of body weight, or between about 0.01 to 100mg/kg of body weight per day, or alternatively, between about 1.0 to 20mg/kg/day. Compounds of this invention may be administered in a singledaily dose, or the total daily dosage may be administered in divideddoses of two, three, or four times daily. In one embodiment, the dailyoral dosage of the active ingredient is between 3 and 600 mg eitheradministered once daily or in divided doses administered twice daily.Alternatively, the active ingredient may be administered in doses of10-20 mg administered twice daily or 40 to 100 mg administered oncedaily. Alternatively, the active ingredient may be administered a doseof 12.5 mg twice a day or 75 mg once a day. Alternatively, the activeingredient may be administered in doses of 3, 10, 30, 100, 300, and 600mg administered either once or twice a day.

Compounds of this invention can be administered in intranasal form viatopical use of suitable intranasal vehicles, or via transdermal routes,using transdermal skin patches. When administered in the form of atransdermal delivery system, the dosage administration will, of course,be continuous rather than intermittent throughout the dosage regimen

The compounds are typically administered in admixture with suitablepharmaceutical diluents, excipients, or carriers (collectively referredto herein as pharmaceutical carriers) suitably selected with respect tothe intended form of administration, that is, oral tablets, capsules,elixirs, syrups and the like, and consistent with conventionalpharmaceutical practices.

For instance, for oral administration in the form of a tablet orcapsule, the active drug component can be combined with an oral,non-toxic, pharmaceutically acceptable, inert carrier such as lactose,starch, sucrose, glucose, methyl cellulose, magnesium stearate,dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like;for oral administration in liquid form, the oral drug components can becombined with any oral, non-toxic, pharmaceutically acceptable inertcarrier such as ethanol, glycerol, water, and the like. Moreover, whendesired or necessary, suitable binders, lubricants, disintegratingagents, and coloring agents can also be incorporated into the mixture.Suitable binders include starch, gelatin, natural sugars such as glucoseor beta-lactose, corn sweeteners, natural and synthetic gums such asacacia, tragacanth, or sodium alginate, carboxymethylcellulose,polyethylene glycol, waxes, and the like. Lubricants used in thesedosage forms include sodium oleate, sodium stearate, magnesium stearate,sodium benzoate, sodium acetate, sodium chloride, and the like.Disintegrators include, without limitation, starch, methyl cellulose,agar, bentonite, xanthan gum, and the like.

The compounds of the present invention can also be administered in theform of liposome delivery systems, such as small unilamellar vesicles,large unilamellar vesicles, and multilamellar vesicles. Liposomes can beformed from a variety of phospholipids, such as cholesterol,stearylamine, or phosphatidylcholines.

Compounds of the present invention may also be coupled with solublepolymers as targetable drug carriers. Such polymers can includepolyvinylpyrrolidone, pyran copolymer,polyhydroxypropylmethacrylamide-phenol,polyhydroxyethylaspartamidephenol, or polyethyleneoxide-polylysinesubstituted with palmitoyl residues. Furthermore, the compounds of thepresent invention may be coupled to a class of biodegradable polymersuseful in achieving controlled release of a drug, for example,polylactic acid, polyglycolic acid, copolymers of polylactic andpolyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid,polyorthoesters, polyacetals, polydihydropyrans, polycyanoacylates, andcrosslinked or amphipathic block copolymers of hydrogels.

Dosage forms (pharmaceutical compositions) suitable for administrationmay contain from about 1 milligram to about 100 milligrams of activeingredient per dosage unit. In these pharmaceutical compositions theactive ingredient will ordinarily be present in an amount of about0.5-95% by weight based on the total weight of the composition.

Gelatin capsules may contain the active ingredient and powderedcarriers, such as lactose, starch, cellulose derivatives, magnesiumstearate, stearic acid, and the like. Similar diluents can be used tomake compressed tablets. Both tablets and capsules can be manufacturedas sustained release products to provide for continuous release ofmedication over a period of hours. Compressed tablets can be sugarcoated or film coated to mask any unpleasant taste and protect thetablet from the atmosphere, or enteric coated for selectivedisintegration in the gastrointestinal tract.

Liquid dosage forms for oral administration can contain coloring andflavoring to increase patient acceptance.

In general, water, a suitable oil, saline, aqueous dextrose (glucose),and related sugar solutions and glycols such as propylene glycol orpolyethylene glycols are suitable carriers for parenteral solutions.Solutions for parenteral administration may contain a water soluble saltof the active ingredient, suitable stabilizing agents, and if necessary,buffer substances. Antioxidizing agents such as sodium bisulfite, sodiumsulfite, or ascorbic acid, either alone or combined, are suitablestabilizing agents. Also used are citric acid and its salts and sodiumEDTA. In addition, parenteral solutions can contain preservatives, suchas benzalkonium chloride, methyl- or propyl-paraben, and chlorobutanol.

Suitable pharmaceutical carriers are described in Remington'sPharmaceutical Sciences, Mack Publishing Company, a standard referencetext in this field.

Representative useful pharmaceutical dosage-forms for administration ofthe compounds of this invention can be illustrated as follows:

Capsules

A large number of unit capsules can be prepared by filling standardtwo-piece hard gelatin capsules each with 100 milligrams of powderedactive ingredient, 150 milligrams of lactose, 50 milligrams ofcellulose, and 6 milligrams magnesium stearate.

Soft Gelatin Capsules

A mixture of active ingredient in a digestible oil such as soybean oil,cottonseed oil or olive oil may be prepared and injected by means of apositive displacement pump into gelatin to form soft gelatin capsulescontaining 100 milligrams of the active ingredient. The capsules shouldbe washed and dried.

Tablets

Tablets may be prepared by conventional procedures so that the dosageunit is 100 milligrams of active ingredient, 0.2 milligrams of colloidalsilicon dioxide, 5 milligrams of magnesium stearate, 275 milligrams ofmicrocrystalline cellulose, 11 milligrams of starch and 98.8 milligramsof lactose. Appropriate coatings may be applied to increase palatabilityor delay absorption.

Dispersion

A spray dried dispersion can be prepared for oral administration bymethods known to one skilled in the art.

Injectable

A parenteral composition suitable for administration by injection may beprepared by stirring 1.5% by weight of active ingredient in 10% byvolume propylene glycol and water. The solution should be made isotonicwith sodium chloride and sterilized.

Suspension

An aqueous suspension can be prepared for oral administration so thateach 5 mL contain 100 mg of finely divided active ingredient, 200 mg ofsodium carboxymethyl cellulose, 5 mg of sodium benzoate, 1.0 g ofsorbitol solution, U.S.P., and 0.025 mL of vanillin.

Where two or more of the foregoing second therapeutic agents areadministered with the compound of the examples, generally the amount ofeach component in a typical daily dosage and typical dosage form may bereduced relative to the usual dosage of the agent when administeredalone, in view of the additive or synergistic effect of the therapeuticagents when administered in combination.

Particularly when provided as a single dosage unit, the potential existsfor a chemical interaction between the combined active ingredients. Forthis reason, when the compound of the examples and a second therapeuticagent are combined in a single dosage unit they are formulated such thatalthough the active ingredients are combined in a single dosage unit,the physical contact between the active ingredients is minimized (thatis, reduced). For example, one active ingredient may be enteric coated.By enteric coating one of the active ingredients, it is possible notonly to minimize the contact between the combined active ingredients,but also, it is possible to control the release of one of thesecomponents in the gastrointestinal tract such that one of thesecomponents is not released in the stomach but rather is released in theintestines. One of the active ingredients may also be coated with amaterial which effects a sustained-release throughout thegastrointestinal tract and also serves to minimize physical contactbetween the combined active ingredients. Furthermore, thesustained-released component can be additionally enteric coated suchthat the release of this component occurs only in the intestine. Stillanother approach would involve the formulation of a combination productin which the one component is coated with a sustained and/or entericrelease polymer, and the other component is also coated with a polymersuch as a low viscosity grade of hydroxypropyl methylcellulose (HPMC) orother appropriate materials as known in the art, in order to furtherseparate the active components. The polymer coating serves to form anadditional barrier to interaction with the other component.

These as well as other ways of minimizing contact between the componentsof combination products of the present invention, whether administeredin a single dosage form or administered in separate forms but at thesame time by the same manner, will be readily apparent to those skilledin the art, once armed with the present disclosure.

Additionally, certain compounds disclosed herein may be useful asmetabolites of other compounds. Therefore, in one embodiment, compoundsmay be useful either as a substantially pure compound, which may alsothen be incorporated into a pharmaceutical composition, or may be usefulas metabolite which is generated after administration of the prodrug ofthat compound. In one embodiment, a compound may be useful as ametabolite by being useful for treating disorders as described herein.

What is claimed is:
 1. A compound of formula I

or an enantiomer, diastereomer, tautomer, or salt thereof wherein: n₁ is0 or 1; R₁ is (C₁-C₁₀)alkyl; R₂ is hydrogen or halo; R₃ is hydrogen orhalo; and R₄ is halo or halo(C₁-C₃)alkyl; provided that the compound isnot:


2. The compound, enantiomer, diastereomer, tautomer, or salt thereof, ofclaim 1, wherein the compound is a compound of formula Ia


3. The compound, enantiomer, diastereomer, tautomer, or salt thereof, ofclaim 1, wherein R₁ is (C₁-C₇)alkyl.
 4. The compound, enantiomer,diastereomer, tautomer, or salt thereof, of claim 1, wherein: n₁ is 1;R₁ is (C₁-C₅)alkyl; R₂ is hydrogen or halo; R₃ is hydrogen or halo; andR₄ is halo or halo(C₁-C₃)alkyl.
 5. The compound, enantiomer,diastereomer, tautomer, or salt thereof, of claim 1, wherein: n₁ is 1;R₁ is methyl or ethyl; R₂ is hydrogen or halo; R₃ is hydrogen or halo;and R₄ is halo or halo(C₁-C₃)alkyl.
 6. The compound, enantiomer,diastereomer, tautomer, or salt thereof, of claim 1, wherein: n₁ is 1;R₁ is methyl or ethyl; R₂ is hydrogen or halo; R₃ is hydrogen or F; andR₄ is halo or halo(C₁-C₃)alkyl.
 7. The compound, enantiomer,diastereomer, tautomer, or salt thereof, of claim 1, wherein: n₁ is 1;R₁ is methyl or ethyl; R₂ is hydrogen or F; R₃ is hydrogen or F; and R₄is halo or halo(C₁-C₃)alkyl.
 8. The compound, enantiomer, diastereomer,tautomer, or salt thereof, of claim 1, wherein the compound is selectedfrom the group consisting of:


9. The compound, enantiomer, diastereomer, tautomer, or salt thereof, ofclaim 8, wherein the compound is selected from the group consisting of:


10. A pharmaceutical composition comprised of a therapeuticallyeffective amount of a compound of claim 1, or an enantiomer, adiastereomer, or a pharmaceutically acceptable salt thereof, andoptionally a pharmaceutically acceptable carrier.
 11. The pharmaceuticalcomposition of claim 10, further comprising a therapeutically effectiveamount of one or more other therapeutically active agents.
 12. Apharmaceutical composition comprising a therapeutically effective amountof a compound of claim 1 and a therapeutically effective amount of adipeptidyl peptidase-IV (DPP4) inhibitor.
 13. The pharmaceuticalcomposition of claim 12, wherein the dipeptidyl peptidase-IV (DPP4)inhibitor is saxagliptin.
 14. A compound, enantiomer, diastereomer,tautomer, or salt thereof, that is:


15. The compound, enantiomer, diastereomer, tautomer, or salt thereof,of claim 1, wherein the compound is a crystalline form of said compound.16. A pharmaceutical composition comprised of a therapeuticallyeffective amount of a compound of claim 14, or an enantiomer, adiastereomer, or a pharmaceutically acceptable salt thereof, andoptionally a pharmaceutically acceptable carrier.
 17. The pharmaceuticalcomposition of claim 16, further comprising a therapeutically effectiveamount of one or more other therapeutically active agents.
 18. Apharmaceutical composition comprising a therapeutically effective amountof a compound of claim 14 and a therapeutically effective amount of adipeptidyl peptidase-IV (DPP4) inhibitor.
 19. The pharmaceuticalcomposition of claim 18, wherein the dipeptidyl peptidase-IV (DPP4)inhibitor is saxagliptin.